NO321835B1 - Process for the preparation of 4-hydroxy-2-oxopyran derivatives which can be used in the preparation of protease inhibitors, as well as intermediates in the process - Google Patents
Process for the preparation of 4-hydroxy-2-oxopyran derivatives which can be used in the preparation of protease inhibitors, as well as intermediates in the process Download PDFInfo
- Publication number
- NO321835B1 NO321835B1 NO20001274A NO20001274A NO321835B1 NO 321835 B1 NO321835 B1 NO 321835B1 NO 20001274 A NO20001274 A NO 20001274A NO 20001274 A NO20001274 A NO 20001274A NO 321835 B1 NO321835 B1 NO 321835B1
- Authority
- NO
- Norway
- Prior art keywords
- acid
- hydroxy
- phenyl
- mixture
- reaction mixture
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 44
- 230000008569 process Effects 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title claims description 11
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title abstract description 7
- 239000000543 intermediate Substances 0.000 title abstract description 3
- VNZOLPIHDIJPBZ-UHFFFAOYSA-N 4-hydroxypyran-2-one Chemical class OC=1C=COC(=O)C=1 VNZOLPIHDIJPBZ-UHFFFAOYSA-N 0.000 title 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 138
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 116
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 96
- 150000001875 compounds Chemical class 0.000 claims description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 49
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 32
- 239000011541 reaction mixture Substances 0.000 claims description 30
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 9
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- QUCVMTKZXVHNNT-CQSZACIVSA-N (3r)-3-hydroxy-3-(2-phenylethyl)hexanoic acid Chemical group CCC[C@](O)(CC(O)=O)CCC1=CC=CC=C1 QUCVMTKZXVHNNT-CQSZACIVSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 230000003213 activating effect Effects 0.000 claims description 5
- 239000012190 activator Substances 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical group C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- 229960000395 phenylpropanolamine Drugs 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229960000281 trometamol Drugs 0.000 claims description 4
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 claims description 2
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 claims description 2
- IJXJGQCXFSSHNL-MRVPVSSYSA-N (2s)-2-amino-2-phenylethanol Chemical compound OC[C@@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-MRVPVSSYSA-N 0.000 claims description 2
- IJXJGQCXFSSHNL-UHFFFAOYSA-N 2-amino-2-phenylethanol Chemical compound OCC(N)C1=CC=CC=C1 IJXJGQCXFSSHNL-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 3
- 238000000605 extraction Methods 0.000 claims 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- 150000007522 mineralic acids Chemical class 0.000 claims 2
- 150000007524 organic acids Chemical class 0.000 claims 2
- 239000003960 organic solvent Substances 0.000 claims 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims 1
- 229940106681 chloroacetic acid Drugs 0.000 claims 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 claims 1
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 claims 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 claims 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 claims 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims 1
- 150000003512 tertiary amines Chemical class 0.000 claims 1
- 241000725303 Human immunodeficiency virus Species 0.000 abstract description 8
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 description 74
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 38
- -1 cyclic ester Chemical class 0.000 description 26
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- 239000000047 product Substances 0.000 description 22
- 238000004809 thin layer chromatography Methods 0.000 description 22
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 239000002002 slurry Substances 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 239000012071 phase Substances 0.000 description 14
- 238000003828 vacuum filtration Methods 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 12
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- 239000008346 aqueous phase Substances 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
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- 239000000741 silica gel Substances 0.000 description 7
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 101150041968 CDC13 gene Proteins 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 6
- LSEJDXFJBNGGBI-UHFFFAOYSA-N 1-(3-nitrophenyl)propan-1-ol Chemical compound CCC(O)C1=CC=CC([N+]([O-])=O)=C1 LSEJDXFJBNGGBI-UHFFFAOYSA-N 0.000 description 5
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- 239000002904 solvent Substances 0.000 description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- ZWWCURLKEXEFQT-UHFFFAOYSA-N dinitrogen pentaoxide Chemical compound [O-][N+](=O)O[N+]([O-])=O ZWWCURLKEXEFQT-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
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- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 241001430294 unidentified retrovirus Species 0.000 description 4
- LSEJDXFJBNGGBI-VIFPVBQESA-N (1s)-1-(3-nitrophenyl)propan-1-ol Chemical compound CC[C@H](O)C1=CC=CC([N+]([O-])=O)=C1 LSEJDXFJBNGGBI-VIFPVBQESA-N 0.000 description 3
- PJKIILWMVXQSGH-UHFFFAOYSA-N 1-(bromomethylsulfanyl)-4-chlorobenzene Chemical compound ClC1=CC=C(SCBr)C=C1 PJKIILWMVXQSGH-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- PVCRXRJCJJIZJW-VIFPVBQESA-N methyl (3s)-3-(3-nitrophenyl)pentanoate Chemical compound COC(=O)C[C@H](CC)C1=CC=CC([N+]([O-])=O)=C1 PVCRXRJCJJIZJW-VIFPVBQESA-N 0.000 description 3
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- QUCVMTKZXVHNNT-UHFFFAOYSA-N 3-hydroxy-3-(2-phenylethyl)hexanoic acid Chemical compound CCCC(O)(CC(O)=O)CCC1=CC=CC=C1 QUCVMTKZXVHNNT-UHFFFAOYSA-N 0.000 description 2
- VZXOZSQDJJNBRC-UHFFFAOYSA-N 4-chlorobenzenethiol Chemical compound SC1=CC=C(Cl)C=C1 VZXOZSQDJJNBRC-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
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- 230000002401 inhibitory effect Effects 0.000 description 2
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- HNBDRPTVWVGKBR-UHFFFAOYSA-N methyl pentanoate Chemical compound CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 2
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- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
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- PRWXGRGLHYDWPS-UHFFFAOYSA-L sodium malonate Chemical compound [Na+].[Na+].[O-]C(=O)CC([O-])=O PRWXGRGLHYDWPS-UHFFFAOYSA-L 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
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- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 2
- 150000003509 tertiary alcohols Chemical class 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
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- 230000002051 biphasic effect Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
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- HOXDXGRSZJEEKN-UHFFFAOYSA-N cycloocta-1,5-diene;rhodium Chemical compound [Rh].C1CC=CCCC=C1 HOXDXGRSZJEEKN-UHFFFAOYSA-N 0.000 description 1
- RCJVRSBWZCNNQT-UHFFFAOYSA-N dichloridooxygen Chemical compound ClOCl RCJVRSBWZCNNQT-UHFFFAOYSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- QDYBCIWLGJMJGO-UHFFFAOYSA-N dinitromethanone Chemical compound [O-][N+](=O)C(=O)[N+]([O-])=O QDYBCIWLGJMJGO-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- RALXFNDYQJBMCF-GOSISDBHSA-N ethyl (5r)-5-hydroxy-3-oxo-5-(2-phenylethyl)octanoate Chemical compound CCOC(=O)CC(=O)C[C@@](O)(CCC)CCC1=CC=CC=C1 RALXFNDYQJBMCF-GOSISDBHSA-N 0.000 description 1
- FFZBULRVXABMOX-UHFFFAOYSA-N ethyl 3-hydroxy-3-(2-phenylethyl)hexanoate Chemical compound CCOC(=O)CC(O)(CCC)CCC1=CC=CC=C1 FFZBULRVXABMOX-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- 239000013067 intermediate product Substances 0.000 description 1
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- 150000002500 ions Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- NWELDCIRFBARNC-UHFFFAOYSA-L magnesium;2-ethylpropanedioate Chemical compound [Mg+2].CCC(C([O-])=O)C([O-])=O NWELDCIRFBARNC-UHFFFAOYSA-L 0.000 description 1
- DVWUPYHFVYOPNV-UHFFFAOYSA-L magnesium;3-ethoxy-3-oxopropanoate Chemical compound [Mg+2].CCOC(=O)CC([O-])=O.CCOC(=O)CC([O-])=O DVWUPYHFVYOPNV-UHFFFAOYSA-L 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- WVUCPRGADMCTBN-UHFFFAOYSA-M potassium;3-ethoxy-3-oxopropanoate Chemical compound [K+].CCOC(=O)CC([O-])=O WVUCPRGADMCTBN-UHFFFAOYSA-M 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 150000003333 secondary alcohols Chemical group 0.000 description 1
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- 238000007873 sieving Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- JSPLKZUTYZBBKA-UHFFFAOYSA-N trioxidane Chemical compound OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
- C07C47/277—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrane Compounds (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
1. Oppfinnelsens område 1. The scope of the invention
Foreliggende oppfinnelse angår nye fremgangsmåter for fremstilling av hydroksylaktoner, og nye mellomprodukter for å fremstille [R-(R<*>,R<*>)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-okso-6-(2-fenyletyl)-6-propyl-2H-pyran-3-yl]propyl]fenyl]-5-(trifluormetyl)-2-pyridinsulfonamid (XIX), som er en proteaseinhibitor anvendelig ved behandling av mennesker infisert med HIV-viruset. The present invention relates to new methods for the production of hydroxylactones, and new intermediates for producing [R-(R<*>,R<*>)]-N-[3-[1-[5,6-dihydro-4-hydroxy -2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide (XIX), which is a protease inhibitor useful in treatment of people infected with the HIV virus.
2. Beskrivelse av beslektet teknikk 2. Description of Related Art
[R-(R<*>,R<*>)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-okso-6-(2-fenyletyl)-6-propyl-2H-pyran-3-yl]propyl]fenyl]-5-(tri-fluormetyl)-2-pyridinsulfonamid (XIX) kan fremstilles ved fremgangsmåten beskrevet i internasjonale publikasjoner [R-(R<*>,R<*>)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl -2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide (XIX) can be prepared by the method described in international publications
WO 95/30670 og WO 94/11361. WO 95/30670 and WO 94/11361.
J. Med Chem., 39(22), 4349 (1996) beskriver den sykliske ester (VI), men i den racemiske form. Dette dokument beskriver også transformasjon av den sykliske ester (VI) til proteaseinhibitoren (XIX), men ved en forskjellig syntetisk reaksjonsvei. J. Med Chem., 39(22), 4349 (1996) describes the cyclic ester (VI), but in the racemic form. This document also describes the transformation of the cyclic ester (VI) into the protease inhibitor (XIX), but by a different synthetic reaction route.
J. Am. Chem. Soc, 111, 3627 (1997) beskriver amino-forbindelsen (XVIII). J. Am. Chem. Soc, 111, 3627 (1997) describes the amino compound (XVIII).
Tetrahedron Letters, 34(2), 277-280 (1993) beskriver en metode for omdannelse av en p-hydroksykarbonylforbindelse til en ring som er lignende den for formlene (VI) og (CVI). p-hydroksykarbonylforbindelsen ifølge den kjente teknikk er en sekundær alkohol, og forbindelsen ifølge foreliggende oppfinnelse er en tertiær alkohol. Fremgangsmåtene er dessuten fullstendig forskjellige ved at fremgangsmåten ifølge Tetrahedron Letters ikke kan anvendes på de tertiære alkoholer (IV) og (CIV) ifølge foreliggende oppfinnelse. Tetrahedron Letters, 34(2), 277-280 (1993) describes a method for converting a p-hydroxycarbonyl compound into a ring similar to that of formulas (VI) and (CVI). The p-hydroxycarbonyl compound according to the prior art is a secondary alcohol, and the compound according to the present invention is a tertiary alcohol. The methods are also completely different in that the method according to Tetrahedron Letters cannot be applied to the tertiary alcohols (IV) and (CIV) according to the present invention.
J. Med. Chem., 39(23), 4630-4642 (1996) beskriver en metode for å fremstille forbindelser lignende forbindelsene med formler (VI) and (CVI), men i racemisk form, fra start-materialer forskjellige fra materialene anvendt ved foreliggende oppfinnelse, og ved en ikke beslektet metode. J. Med. Chem., 39(23), 4630-4642 (1996) describes a method for preparing compounds similar to the compounds of formulas (VI) and (CVI), but in racemic form, from starting materials different from the materials used in the present invention, and by an unrelated method.
Internasjonal publikasjon WO 95/14012 beskriver en syklisk forbindelse lignende de sykliske forbindelser (VI), (XVII) og (XXV) ifølge foreliggende oppfinnelse, men i racemisk form. Fremgangsmåten ifølge foreliggende oppfinnelse produserer disse forbindelser i optisk ren form. International publication WO 95/14012 describes a cyclic compound similar to the cyclic compounds (VI), (XVII) and (XXV) according to the present invention, but in racemic form. The method according to the present invention produces these compounds in optically pure form.
O ppsummering av oppfinnelsen Summary of the invention
Foreliggende oppfinnelse angår (R)-3-hydroksy-3-(2-fenyletyl)heksansyre (IV) og farmasøytisk akseptable salter av denne. The present invention relates to (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid (IV) and pharmaceutically acceptable salts thereof.
Oppfinnelsen angår også (6R)-5,6-dihydro-4-hydroksy-6-[l-(2-fenyl)etyl]-6-propyl-2H-pyran-2-on. The invention also relates to (6R)-5,6-dihydro-4-hydroxy-6-[1-(2-phenyl)ethyl]-6-propyl-2H-pyran-2-one.
Oppfinnelsen angår dessuten [3a(R),6(R)]-5,6-dihydro-4-hydroxy-3-[l-(3-nitrofenyl)propyl]-6-[l-(2-fenyl)etyl]-6-propyl-2H-pyran-2-on (XVII). The invention also relates to [3a(R),6(R)]-5,6-dihydro-4-hydroxy-3-[1-(3-nitrophenyl)propyl]-6-[1-(2-phenyl)ethyl] -6-propyl-2H-pyran-2-one (XVII).
Oppfinnelsen angår videre (S)-metyl-3-(3-nitrofenyl)-pentanoat. The invention further relates to (S)-methyl-3-(3-nitrophenyl)-pentanoate.
Oppfinnelsen angår også [3a(R),6(R)]-5,6-dihydro-4-hydroxy-3-t(2)-l-(3-nitrofenylJpropenyl]-6-[l-(2-fenyl)etyl]-6-propyl-2H-pyran-2-on. The invention also relates to [3a(R),6(R)]-5,6-dihydro-4-hydroxy-3-t(2)-1-(3-nitrophenylJpropenyl)-6-[1-(2-phenyl) ethyl]-6-propyl-2H-pyran-2-one.
Oppfinnelsen angår også en fremgangsmåte for fremstilling av hydroksylaktonet med formel (CVI) The invention also relates to a method for producing the hydroxylactone of formula (CVI)
hvor Ri er: where Ri is:
Ci-Cg-alkyl, C 1 -C 8 alkyl,
sykloheksyl, cyclohexyl,
fenyl, phenyl,
-CH2-CH2~4»Ri-1 / hvor Ri_i er -0H (og beskyttede former av denne), -NH2 (og beskyttede former av denne), -CH2-CH2~4»Ri-1 / where Ri_i is -OH (and protected forms thereof), -NH2 (and protected forms thereof),
-H, -H,
-NH-CO-CH3, -NH-CO-CH3,
-N(-C0-CH3) 2i -N(-CO-CH 3 ) 2 i
hvor R2 er: where R2 is:
Ci-C6-alkyl, C 1 -C 6 alkyl,
sykloheksyl, cyclohexyl,
fenyl, phenyl,
-CH2~CH2-^R2-1 r hvor R2-i er -0H (og beskyttede former av denne), -NH2 (og beskyttede former av denne), -CH2~CH2-^R2-1 r where R2-i is -OH (and protected forms thereof), -NH2 (and protected forms thereof),
-H, -H,
-NH-CO-CH3, -NH-CO-CH3,
-N(-CO-CH3) 2i -N(-CO-CH 3 ) 2 i
hvilken fremgangsmåte omfatter at: which method comprises that:
(1) et salt med formel (CIV) bringes i kontakt med en syre for å produsere en fri syre, (2) den frie syre ekstraheres fra reaksjonsblandingen, (3) den frie syre bringes i kontakt med et aktiveringsmiddel, (4) reaksjonsblandingen av fri syre/aktiveringsmiddel bringes i kontakt med malonatmonoester og et divalent metall, (5) reaksjonsblandingen fra trinn (4) bringes i kontakt med en syre, (6) reaksjonsblandingen fra trinn (5) bringes i kontakt med en base i nærvær av en Ci-C4-a lkohol, THF eller (1) a salt of formula (CIV) is contacted with an acid to produce a free acid, (2) the free acid is extracted from the reaction mixture, (3) the free acid is contacted with an activator, (4) the free acid/activator reaction mixture is contacted with malonate monoester and a divalent metal, (5) contacting the reaction mixture from step (4) with an acid, (6) contacting the reaction mixture from step (5) with a base in the presence of a C 1 -C 4 alcohol, THF or
DMF. DMF.
Oppfinnelsen angår dessuten en fremgangsmåte for fremstilling av hydroksylaktonet med formel (CVI) The invention also relates to a method for producing the hydroxylactone of formula (CVI)
hvor Ri er: where Ri is:
Ci-Cg-alkyl, C 1 -C 8 alkyl,
sykloheksyl, cyclohexyl,
fenyl, phenyl,
-CH2-CH2-<t>Ri-i, hvor R1-1 er -OH (og beskyttede former av denne), -NHa (og beskyttede former av denne), -CH2-CH2-<t>Ri-i, where R1-1 is -OH (and protected forms thereof), -NHa (and protected forms thereof),
-H, -H,
-NH-CO-CH3, -N(-CO-CH3)2; -NH-CO-CH 3 , -N(-CO-CH 3 ) 2 ;
hvor R2 er: where R2 is:
(VCe-alkyl, (VCe-alkyl,
sykloheksyl, cyclohexyl,
fenyl, phenyl,
-CH2-CHj-<t»R2.1( hvor R2.! er -OH (og beskyttede former av denne), -NHa (og beskyttede former av denne), -CH2-CHj-<t»R2.1( where R2.! is -OH (and protected forms thereof), -NHa (and protected forms thereof),
-H, -H,
-NH-CO-CH3, -N(-C0-CHj)i; hvilken fremgangsmåte omfatter at: (1) anionet med formel (CIV) eller den frie syreform av dette bringes i kontakt med et aktiveringsmiddel, (2) reaksjonsblandingen av fri syre/aktiveringsmiddel bringes i kontakt med malonatmonoester og et divalent metall, (3) reaksjonsblandingen fra trinn (2) bringes i kontakt med en syre, (4) reaksjonsblandingen fra trinn (3) bringes i kontakt med en base i nærvær av en C^-C^-alkohol, THF eller -NH-CO-CH 3 , -N(-CO-CH 1 ) i ; which method comprises that: (1) the anion of formula (CIV) or the free acid form thereof is contacted with an activating agent, (2) the free acid/activating agent reaction mixture is contacted with malonate monoester and a divalent metal, (3) the reaction mixture from step (2) is contacted with an acid, (4 ) the reaction mixture from step (3) is contacted with a base in the presence of a C₁-C₂ alcohol, THF or
DMF. DMF.
Detaljert beskrivelse av oppfinnelsen Detailed description of the invention
Foreliggende oppfinnelse angår to nye fremgangsmåter for fremstilling av hydroksylaktoner, samt nye mellomprodukter for, etter ytterligere reaksjonstrinn, å fremstille [R-(R*,R*) ] -N-[3-[I-[5,6-dihydro-4-hydroxy-2-okso-6-(2-fenyletyl)-6-propyl-2H-pyran-3-yl]propyl]fenyl]-5-(trifluormetyl) - 2-pyridinsulfonamid (XIX), som er kjent som en proteaseinhibitor og som er anvendelig ved behandling av mennesker infisert The present invention relates to two new methods for the production of hydroxylactones, as well as new intermediate products for, after further reaction steps, to produce [R-(R*,R*) ] -N-[3-[I-[5,6-dihydro-4 -hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide (XIX), which is known as a protease inhibitor and which is applicable in the treatment of infected humans
med HIV. with HIV.
Skjema A viser transformasjon av ketonet (I) til den tilsvarende ketoester (II), til den tilsvarende syre (III), til det tilsvarende salt (IV), til den tilsvarende ketoalkohol (V) og til sist til den tilsvarende sykliske ester (VI); se også eksempler 1-4 og den foretrukne fremgangsmåte, eksempel 18. Scheme A shows transformation of the ketone (I) to the corresponding ketoester (II), to the corresponding acid (III), to the corresponding salt (IV), to the corresponding ketoalcohol (V) and finally to the corresponding cyclic ester (VI ); see also Examples 1-4 and the preferred method, Example 18.
Skjema B viser transformasjon av 4-klortiofenol (VII) til den tilsvarende kloreter (VIII), til den tilsvarende bifenylforbindelse (IX); se også eksempler 5 og 6. Scheme B shows transformation of 4-chlorothiophenol (VII) to the corresponding chloroether (VIII), to the corresponding biphenyl compound (IX); see also examples 5 and 6.
Skjema C viser kondensasjon av bifenylforbindelsen (IX) med saltet (IV) for å gi estereteren (X), og transformasjonene av estereteren (X) til den tilsvarende alkohol (XI) og til det tilsvarende aldehyd (XII). Også vist er koplingen av den optisk rene nitroester (XIII) med aldehydet (XII) for å produsere den tilsvarende nitroeter (XIV); se også eksempler 7-10. Scheme C shows the condensation of the biphenyl compound (IX) with the salt (IV) to give the ester ether (X), and the transformations of the ester ether (X) to the corresponding alcohol (XI) and to the corresponding aldehyde (XII). Also shown is the coupling of the optically pure nitroester (XIII) with the aldehyde (XII) to produce the corresponding nitroether (XIV); see also examples 7-10.
Skjema D viser transformasjonene av nitroeteren (XIV) til det tilsvarende nitroketon (XV), til den tilsvarende nitroalkohol (XVI), til den tilsvarende nitro-a,p-umettede ester (XVII), til den tilsvarende aminoforbindeIse (XVIII) og til den tilsvarende proteaseinhibitor (XIX); se også eksempler 11-15. Scheme D shows the transformations of the nitroether (XIV) into the corresponding nitroketone (XV), into the corresponding nitroalcohol (XVI), into the corresponding nitro-a,p-unsaturated ester (XVII), into the corresponding amino compound (XVIII) and into the corresponding protease inhibitor (XIX); see also examples 11-15.
Skjema E viser fremstilling av den optisk rene nitroester (XIII) som anvendes i skjema C. Skjema E viser den optiske oppløsning av den racemiske 1-(3-nitrofenyl)propanol (XX) for å produsere den tilsvarende optisk rene l-(3-nitrofenyl)propanol (XXI) og dens transformasjon til det tilsvarende metylsulfonat (XXII), til den tilsvarende diester (XXIII), til den tilsvarende nitrosyre (XXIV) og til den tilsvarende optisk rene nitroester (XIII); se også frem-stillinger 1-5. Scheme E shows the preparation of the optically pure nitroester (XIII) used in Scheme C. Scheme E shows the optical resolution of the racemic 1-(3-nitrophenyl)propanol (XX) to produce the corresponding optically pure 1-(3- nitrophenyl)propanol (XXI) and its transformation to the corresponding methyl sulfonate (XXII), to the corresponding diester (XXIII), to the corresponding nitro acid (XXIV) and to the corresponding optically pure nitroester (XIII); see also exhibits 1-5.
Skjema F viser en alternativ, og foretrukket, reaksjonsvei for transformasjon av den sykliske ester (VI) til den tilsvarende nitro-a,p-umettede ester (XVII). Den sykliske ester (VI) er blitt tilført m-nitrofenylgruppen for å bli Scheme F shows an alternative, and preferred, reaction pathway for transformation of the cyclic ester (VI) to the corresponding nitro-a,p-unsaturated ester (XVII). The cyclic ester (VI) has been added to the m-nitrophenyl group to become
6(R)-olefinet (XXV), se eksempel 16, som hydrogeneres med den passende katalysator for å produsere den reduserte forbindelse, den nitro-a,p-umettede ester (XVII), se eksempel 17. Den The 6(R)-olefin (XXV), see Example 16, which is hydrogenated with the appropriate catalyst to produce the reduced compound, the nitro-α,p-unsaturated ester (XVII), see Example 17. The
nitro-a,<p->umettede ester (XVII) transformeres deretter til proteaseinhibitoren (XIX), som diskutert ovenfor. nitro-α,<p->unsaturated ester (XVII) is then transformed into the protease inhibitor (XIX), as discussed above.
Skjema G viser en fremgangsmåte for å produsere optisk rene hydroksylaktoner med formel (CVI). Fremgangsmåten for transformasjonen av saltet med formel (CIV) til hydroksylaktonet med formel (CVI) følger eksempler 1-4 og 18. Hydroksyl- og aminogruppene på startmaterialet (CI) kan beskyttes, hvilket er vel kjent for fagfolk. Disse beskyttel-sesgrupper kan fjernes på forskjellige steder i de etter-følgende fremgangsmåtetrinn ved hjelp av metoder vel kjent for fagfolk, eller utsettes til slutten av prosessen hvor de vil fjernes for å produsere det ønskede produkt. Det er åpenbart for en fagperson at det finnes forskjellige måter for å produsere det optisk rene (CIV) . Det er ikke viktig hvordan oppløsningen ifølge eksempel 3, som produserer det optisk rene (CIV), utføres. Oppfinnelsen her er omdannelsen av det optisk rene (CIV) til det optisk rene (CVI). Scheme G shows a method for producing optically pure hydroxylactones of formula (CVI). The procedure for the transformation of the salt of formula (CIV) to the hydroxylactone of formula (CVI) follows Examples 1-4 and 18. The hydroxyl and amino groups of the starting material (CI) can be protected, as is well known to those skilled in the art. These protecting groups can be removed at various places in the subsequent process steps by means of methods well known to those skilled in the art, or postponed until the end of the process where they will be removed to produce the desired product. It will be obvious to one skilled in the art that there are different ways to produce the optically pure (CIV). It is not important how the resolution according to Example 3, which produces the optically pure (CIV), is carried out. The invention here is the conversion of the optically pure (CIV) to the optically pure (CVI).
Syren (III) danner baseaddisjonssalter når den reageres med baser av tilstrekkelig styrke. De farmasøytisk akseptable salter inkluderer både uorganiske og organiske baser. De farmasøytiske salter er foretrukket fremfor de frie syrer fordi de produserer forbindelser som er mer vannløselige og mer krystallinske. De foretrukne farmasøytisk akseptable salter inkluderer f.eks. salter av de følgende baser: hydroksid, ammoniakk, trometamin (THAM), 2-amino-2-(hydroksy-metyl)-1,3-propandiol, (1R,2S)-norefedrin, (IS,2R)-norefedrin, (R)-2-amino-2-fenyletanol, (S)-2-amino-2-fenyletanol, (R)-1-fenyletylamin og (S)-1-fenyletylamin. Det er foretrukket at saltet er (IR,2S)-norefedrinsaltet. The acid (III) forms base addition salts when reacted with bases of sufficient strength. The pharmaceutically acceptable salts include both inorganic and organic bases. The pharmaceutical salts are preferred over the free acids because they produce compounds that are more water soluble and more crystalline. The preferred pharmaceutically acceptable salts include e.g. salts of the following bases: hydroxide, ammonia, tromethamine (THAM), 2-amino-2-(hydroxymethyl)-1,3-propanediol, (1R,2S)-norephedrine, (IS,2R)-norephedrine, ( R)-2-amino-2-phenylethanol, (S)-2-amino-2-phenylethanol, (R)-1-phenylethylamine and (S)-1-phenylethylamine. It is preferred that the salt is the (IR,2S)-norephedrine salt.
[R-(R<*>,R<*>)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-okso-6-(2-fenyletyl)-6-propyl-2H-pyran-3-yl]propyl]fenyl]-5-(tri-fluormetyl)-2-pyridinsulfonamid (XIX), forbindelsen ifølge eksempel 15, er kjent for å være anvendelig ved behandling av mennesker infisert med HIV, se internasjonale publikasjoner WO 95/30670 og WO 94/11361. Denne forbindelsen inhiberer retrovirusproteaser og inhiberer således replikasjonen av viruset. Forbindelsen er anvendelig for inhibering av human retrovirusprotease. Forbindelsen er anvendelig ved behandling av humane pasienter infisert med et humant [R-(R<*>,R<*>)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl -2H-pyran-3-yl]propyl]phenyl]-5-(tri-fluoromethyl)-2-pyridinesulfonamide (XIX), the compound of Example 15, is known to be useful in the treatment of humans infected with HIV, see International publications WO 95/30670 and WO 94/11361. This compound inhibits retrovirus proteases and thus inhibits the replication of the virus. The compound is useful for inhibiting human retrovirus protease. The compound is useful in the treatment of human patients infected with a human
retrovirus, slik som humant immunsviktvirus (stammer av HIV-1 eller HIV-2) eller humane T-celleleukemivirus (HTLV-I eller HTLV-II) som resulterer i ervervet immunsviktsyndrom (AIDS) og/eller beslektede sykdommer. retroviruses, such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) that result in acquired immunodeficiency syndrome (AIDS) and/or related diseases.
Pasienter som skal behandles, vil være de individer som (1) er infisert med én eller flere stammer av et humant retrovirus, som bestemt ved tilstedeværelse av enten målbart virusantistoff eller antigen i serum, og (2) i tilfellet med HIV, som enten har en asymptomatisk HIV-infeksjon eller en symptomatisk AIDS-definerende infeksjon, slik som (a) diss-eminert histoplasmose, (b) isopsoriasis, (c) bronkial og pulmonal candidiasis, inkludert pneumocystisk pneumoni, (d) non-Hodgkins lymfom eller (e) Kaposis sarkom, og som er mindre enn 30 år gamle; eller som har en absolutt CD4<+->lymfo-cyttelling mindre enn 500/mm<3> i det perifere blod. Behandling vil bestå av opprettholdelse av et inhibitorisk nivå av forbindelsen i pasienten til enhver tid. Patients to be treated will be those individuals who (1) are infected with one or more strains of a human retrovirus, as determined by the presence of either measurable viral antibody or antigen in serum, and (2) in the case of HIV, who have either an asymptomatic HIV infection or a symptomatic AIDS-defining infection, such as (a) disseminated histoplasmosis, (b) isopsoriasis, (c) bronchial and pulmonary candidiasis, including pneumocystis pneumonia, (d) non-Hodgkin's lymphoma, or (e ) Kaposi's sarcoma, and who are less than 30 years old; or who have an absolute CD4<+->lymphocyte count less than 500/mm<3> in the peripheral blood. Treatment will consist of maintaining an inhibitory level of the compound in the patient at all times.
Forbindelsen er anvendelig for behandling av pasienter infisert med humant immunsviktvirus (HIV) som resulterer i ervervet immunsviktsyndrom (AIDS) og beslektede sykdommer. For denne indikasjon kan disse forbindelser administreres oralt, intranasalt, transdermalt, subkutant og parenteralt (inkludert intramuskulært og intravenøst), i doser på 0,1 mg til 100 mg/kg kroppsvekt pr. dag. Det er foretrukket at forbindelsene administreres oralt. The compound is useful for treating patients infected with human immunodeficiency virus (HIV) resulting in acquired immunodeficiency syndrome (AIDS) and related diseases. For this indication, these compounds can be administered orally, intranasally, transdermally, subcutaneously and parenterally (including intramuscularly and intravenously), in doses of 0.1 mg to 100 mg/kg body weight per day. It is preferred that the compounds are administered orally.
Fagfolk vil vite hvordan forbindelsen skal formuleres til passende farmasøytiske doseringsformer. Eksempler på doseringsformer inkluderer orale formuleringer, slik som tabletter eller kapsler, eller parenterale formuleringer, slik som sterile løsninger. Those skilled in the art will know how to formulate the compound into suitable pharmaceutical dosage forms. Examples of dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.
Når forbindelsen administreres oralt, er en effektiv mengde fra ca. 0,1 mg til 100 mg/kg kroppsvekt pr. dag. Det er foretrukket at den effektive mengde er fra ca. 10 til 100 mg/kg kroppsvekt pr. dag. Det er mer foretrukket at mengden er fra ca. 30 mg til 90 mg/kg kroppsvekt. Det er foretrukket at forbindelsene administreres 2-5 ganger daglig, mer foretrukket tre ganger daglig. Det er foretrukket at dosen er fra ca. 2700 mg/dag til ca. 4500 mg/dag. When the compound is administered orally, an effective amount is from about 0.1 mg to 100 mg/kg body weight per day. It is preferred that the effective amount is from approx. 10 to 100 mg/kg body weight per day. It is more preferred that the amount is from approx. 30 mg to 90 mg/kg body weight. It is preferred that the compounds are administered 2-5 times daily, more preferably three times daily. It is preferred that the dose is from approx. 2700 mg/day to approx. 4500 mg/day.
Enten faste eller flytende doseringsformer kan prepareres for oral administrering. Det er foretrukket at forbindelsene gis i fast doseringsform, mer foretrukket som en kapsel. Either solid or liquid dosage forms can be prepared for oral administration. It is preferred that the compounds are given in solid dosage form, more preferably as a capsule.
Når forbindelsene administreres parenteralt, kan de gis ved injeksjon eller ved intravenøs infusjon. En effektiv mengde er fra ca. 0,1 mg til 100 mg/kg kroppsvekt pr. dag. Parenterale løsninger prepareres ved oppløsning av forbindelsene i et vandig vehikkel, etterfulgt av filtersterilisering av løsningen før den plasseres i en passende forseglbar beholder eller ampulle. Parenterale suspensjoner prepareres på vesentlig den samme måte, med unntak av at det benyttes en steril suspensjon og forbindelsen steriliseres med etylenoksid eller en egnet gass før den suspenderes i vehiklet. When the compounds are administered parenterally, they can be given by injection or by intravenous infusion. An effective amount is from approx. 0.1 mg to 100 mg/kg body weight per day. Parenteral solutions are prepared by dissolving the compounds in an aqueous vehicle, followed by filter sterilization of the solution before placing it in a suitable sealable container or ampoule. Parenteral suspensions are prepared in essentially the same way, with the exception that a sterile suspension is used and the compound is sterilized with ethylene oxide or a suitable gas before it is suspended in the vehicle.
Den nøyaktige administreringsmåte, dose eller admini-streringshyppighet vil lett bestemmes av fagfolk og er av-hengig av alder, vekt, generell fysisk tilstand og/eller andre kliniske symptomer som er spesifikke for pasienten som skal behandles. The exact mode of administration, dose or frequency of administration will be readily determined by those skilled in the art and will depend on age, weight, general physical condition and/or other clinical symptoms specific to the patient to be treated.
Definisjoner og konvensjoner Definitions and conventions
Definisjonene og forklaringene nedenfor er for betegnelsene anvendt gjennom hele dette dokument, inkludert både beskrivelsen og kravene. The definitions and explanations below are for the terms used throughout this document, including both the description and the requirements.
Definisjoner Definitions
Alle temperaturer er i grader Celsius. All temperatures are in degrees Celsius.
TLC refererer til tynnsjiktskromatografi. TLC refers to thin layer chromatography.
HPLC refererer til høytrykksvæskekromatografi; 4,6 x 250 mm Zorbax C-8-kolonne, mobil fase A = metanol, mobil fase B = 6,5 g t-butylammoniumhydroksid i vann, pH til 4,0 med eddiksyre, gradient fra 65/35 A/B til 70/30 A/B i løpet av 20 minutter, deretter isokratisk 70/30 A/B i 5 minutter, deretter gradient til 90/10 A/B i løpet av 2 0 minutter; strømningshastighet er 1,0 ml/minutt; UV-deteksjon ved 254 nm. HPLC refers to high pressure liquid chromatography; 4.6 x 250 mm Zorbax C-8 column, mobile phase A = methanol, mobile phase B = 6.5 g t-butylammonium hydroxide in water, pH to 4.0 with acetic acid, gradient from 65/35 A/B to 70/30 A/B over 20 min, then isocratic 70/30 A/B over 5 min, then gradient to 90/10 A/B over 2 0 min; flow rate is 1.0 ml/minute; UV detection at 254 nm.
THF refererer til tetrahydrofuran. THF refers to tetrahydrofuran.
DMF refererer til dimetylformamid. DMF refers to dimethylformamide.
MTBE refererer til metyl-t-butyleter. MTBE refers to methyl-t-butyl ether.
DMSO refererer til dimetylsulfoksid. DMSO refers to dimethyl sulfoxide.
Saltvann refererer til en mettet, vandig natrium-kloridløsning. Salt water refers to a saturated, aqueous sodium chloride solution.
Kromatografi {kolonne- og flashkromatografi) refererer til rensing/separasjon av forbindelser uttrykt ved (støttemateriale, elueringsmiddel). Det er underforstått at de passende fraksjoner sammenslås og konsentreres for å gi den ønskede forbindelse (forbindelser). Chromatography {column and flash chromatography) refers to the purification/separation of compounds expressed by (support material, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
CMR refererer til C-13-magnetisk resonans-spektro-skopi, kjemiske skift er gitt i ppm (8) nedstrøms fra TMS. CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are given in ppm (8) downstream from TMS.
NMR refererer til kjerne(proton)-magnetisk resonans-spektroskopi, kjemiske skift er gitt i ppm (8) nedstrøms fra tetrametylsilan. NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are given in ppm (8) downstream from tetramethylsilane.
MS refererer til massespektrometri uttrykt som m/e, m/z eller masse-/ladningsenhet. [M + H] + refererer til det positive ion av et stamatom pluss et hydrogenatom. EI refererer til elektronstøt. CI refererer til kjemisk ionisering. FAB refererer til hurtig atombombardement. MS refers to mass spectrometry expressed as m/e, m/z or mass/charge unit. [M + H] + refers to the positive ion of a parent atom plus a hydrogen atom. EI refers to electron impact. CI refers to chemical ionization. FAB refers to fast nuclear bombardment.
Eter refererer til dietyleter. Ether refers to diethyl ether.
Farmasøytisk akseptabel refererer til de egenskaper og/eller stoffer som er akseptable for pasienten fra et farma-kologisk/toksikologisk synspunkt, og for den produserende farmasøytiske kjemiker fra et fysikalsk/kjemisk synspunkt angående sammensetning, formulering, stabilitet, pasient-akseptering og biotilgjengelighet. Pharmaceutically acceptable refers to the properties and/or substances that are acceptable to the patient from a pharmacological/toxicological point of view, and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
Når det anvendes løsningsmiddelpar,. er forholdet mellom de anvendte løsningsmidler volum/volum (v/v). When solvent pairs are used, is the ratio between the solvents used volume/volume (v/v).
Når oppløseligheten av et fast materiale i et løsningsmiddel anvendes, er forholdet mellom det faste materialet og løsningsmidlet vekt/volum. When the solubility of a solid material in a solvent is used, the ratio between the solid material and the solvent is weight/volume.
Forbindelse refererer til [R-(R<*>,R<*>)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-okso-6-(2-fenyletyl)-6-propyl-2H-pyran-3-yllpropyl]fenyl]-5-(trifluormetyl)-2-pyridinsulfonamid (XIX). Compound refers to [R-(R<*>,R<*>)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)- 6-Propyl-2H-pyran-3-ylpropyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide (XIX).
Alkyl refererer til C1-C4-alkyl, inkludert både rettkjedede og forgrenede isomerer. Alkyl refers to C1-C4 alkyl, including both straight and branched chain isomers.
WL refererer til etyl og t-butyl. WL refers to ethyl and t-butyl.
Eksempler Examples
Uten ytterligere utdyping antas det at en fagperson ved anvendelse av den foregående beskrivelse kan utøve foreliggende oppfinnelse i dens bredeste omfang. De følgende detaljerte eksempler beskriver måten for å fremstille de forskjellige forbindelser og/eller utføre de forskjellige fremgangsmåter ifølge oppfinnelsen, og skal kun oppfattes som illustrerende for den foregående beskrivelse. Fagfolk vil hurtig finne passende variasjoner av prosedyrene, både med hensyn til reaktanter og reaksjonsbetingelser og teknikker. Without further elaboration, it is assumed that a person skilled in the art, by applying the preceding description, can practice the present invention in its widest scope. The following detailed examples describe the way to prepare the various compounds and/or carry out the various methods according to the invention, and should only be understood as illustrative of the preceding description. Those skilled in the art will quickly find suitable variations of the procedures, both with regard to reactants and reaction conditions and techniques.
Fremstilling 1 Production 1
Oppløsning av ( ±)- 1-( 3- nitrofenyl) propanol ( XX) ved omdannelse til ( S)- 1-( 3- nitrofenyl) propanol ( XXI) og ( R)- 1-( 3- nitrofenyl) propanolacetat Dissolution of ( ±)- 1-( 3- nitrophenyl) propanol ( XX) by conversion to ( S)- 1-( 3- nitrophenyl) propanol ( XXI) and ( R)- 1-( 3- nitrophenyl) propanol acetate
Celitt-understøttet PS-30-lipase (Amano, 24 g) og isopropenylacetat (22,00 ml, 0,20 mol) tilsettes til (±)-l-(3-nitrofenyl)propanol (XX, 24,00 g, 0,13 mol) i MTBE (240 ml). Blandingen omrøres ved 20-25 °C i 2 dager. Ved slutten av denne tid fjernes katalysatoren ved filtrering, katalysatorkaken vaskes med eter, og blandingen konsentreres under redusert trykk for å gi en acetat-alkoholblanding. Separering av blandingen ved kiselgelkromatografi gir (R)-1-(3-nitrofenyl)-propanol acetat (13,03 g) , [a]D = +68,7° (etanol, c = 1) , og (S)-1-(3-nitrofenyl)propanol (10,7 g), [aJD = -33,0° (etanol, Celite-supported PS-30 lipase (Amano, 24 g) and isopropenyl acetate (22.00 mL, 0.20 mol) are added to (±)-1-(3-nitrophenyl)propanol (XX, 24.00 g, 0 .13 mol) in MTBE (240 mL). The mixture is stirred at 20-25 °C for 2 days. At the end of this time, the catalyst is removed by filtration, the catalyst cake is washed with ether, and the mixture is concentrated under reduced pressure to give an acetate-alcohol mixture. Separation of the mixture by silica gel chromatography gives (R)-1-(3-nitrophenyl)-propanol acetate (13.03 g), [a]D = +68.7° (ethanol, c = 1) , and (S)- 1-(3-nitrophenyl)propanol (10.7 g), [αJD = -33.0° (ethanol,
c = 1) . c = 1).
Fremstilling 2 Manufacturing 2
( S)- 1-( 3- nitrofenyl) propanolmesylat ( XXII) ( S )- 1-( 3- nitrophenyl) propanol mesylate ( XXII)
Diisopropyletylamin (1,07 g, 8,3 mmol) tilsettes til en blanding av (S)-1-(3-nitrofenyl)propanol (XXI, fremstilling 1, lg, 5,5 mmol) i metylenklorid (20 ml). Blandingen avkjøles til -20 °C, og metansulfonylklorid (0,69 g, 6,02 mmol) til- . settes. Reaksjonsblandingen holdes ved -20 <*>C i 10 minutter og deretter ved 0 °C i 40 minutter. Reaksjonsblandingen fortynnes med metylenklorid, natriumbikarbonat (5 %) tilsettes, og fasene separeres. Metylenkloridet avdampes for å gi tittelforbindelsen, [a]D = -79,9° (etanol, c = 1) ; TLC (kiselgel GF, etylacetat/heksan, 20/80), Rf = 0,19; NMR (CDC13, TMS), 0,96-1,01, 1,88-2,17, 2,89, 5,54-5,59, 7,57-7,62, 7,70-7,73 og 8,20-8,24 5. Diisopropylethylamine (1.07 g, 8.3 mmol) is added to a mixture of (S)-1-(3-nitrophenyl)propanol (XXI, Preparation 1, 1g, 5.5 mmol) in methylene chloride (20 mL). The mixture is cooled to -20 °C, and methanesulfonyl chloride (0.69 g, 6.02 mmol) is added. is set. The reaction mixture is kept at -20<*>C for 10 minutes and then at 0°C for 40 minutes. The reaction mixture is diluted with methylene chloride, sodium bicarbonate (5%) is added, and the phases are separated. The methylene chloride is evaporated to give the title compound, [α]D = -79.9° (ethanol, c = 1); TLC (silica gel GF, ethyl acetate/hexane, 20/80), Rf = 0.19; NMR (CDCl 3 , TMS), 0.96-1.01, 1.88-2.17, 2.89, 5.54-5.59, 7.57-7.62, 7.70-7.73 and 8.20-8.24 5.
Fremstilling 3 Manufacturing 3
fS\- dimetvl- l- r1- t 3- nitrofenvl^ proovlImalonat fXXIII) fS\- dimetvl- l- r1- t 3- nitrophenvl^ proovlImalonate fXXIII)
En oppløsning av natriumetoksid (1,0 M) prepareres ved oppløsning av natriummetall (1,27 g, 0,055 mol) i absolutt etanol (55 ml). DietyImalonat (8,84 g, 0,055 mol) tilsettes til denne løsningen ved 0 °C. (S)-l-(3-nitrofenyl)propanolmesylat (XXII, fremstilling 2, 1,43 g, 5,5 mmol) tilsettes dråpevis til løsningen av natriummalonat (6,4 ml, 6,4 mmol) ved -20 °C. Etter 2 timer ved 20-25 "C tilsettes en ytterligere aliquot av natriummalonat (5 ml, 5,0 mmol) til reaksjonsblandingen, som deretter omrøres over natten ved 20-25 °C. Reaksjonsblandingen konsentreres og deles mellom etylacetat og saltsyre (1 N). Den organiske fase separeres, og løsnings-midlet fjernes for å gi et råprodukt som kromatograferes (kiselgel; etylacetat/heksan, 10/90) for å gi tittelforbindelsen, [<x]D = +19,4° (etanol, c = 1); TLC (kiselgel GF, etylacetat/heksan, 20/80), Rf = 0,48; NMR (CDC13, TMS) 0,70-0,75, 0,96-1,00, 1,27-1,32, 1,56-1,88, 3,37-3,45, 3,65-3,69, 3,86-3,96, 4,21-4,28, 7,44-7,49, 7,54-7,57 og 8,08-8,11 8. A solution of sodium ethoxide (1.0 M) is prepared by dissolving sodium metal (1.27 g, 0.055 mol) in absolute ethanol (55 mL). DietyImalonate (8.84 g, 0.055 mol) is added to this solution at 0 °C. (S)-1-(3-nitrophenyl)propanol mesylate (XXII, Preparation 2, 1.43 g, 5.5 mmol) is added dropwise to the solution of sodium malonate (6.4 mL, 6.4 mmol) at -20 °C . After 2 h at 20-25 °C, a further aliquot of sodium malonate (5 mL, 5.0 mmol) is added to the reaction mixture, which is then stirred overnight at 20-25 °C. The reaction mixture is concentrated and partitioned between ethyl acetate and hydrochloric acid (1 N ).The organic phase is separated and the solvent is removed to give a crude product which is chromatographed (silica gel; ethyl acetate/hexane, 10/90) to give the title compound, [<x]D = +19.4° (ethanol, c = 1); TLC (silica gel GF, ethyl acetate/hexane, 20/80), Rf = 0.48; NMR (CDCl 3 , TMS) 0.70-0.75, 0.96-1.00, 1.27- 1.32, 1.56-1.88, 3.37-3.45, 3.65-3.69, 3.86-3.96, 4.21-4.28, 7.44-7, 49, 7.54-7.57 and 8.08-8.11 8.
Fremstilling 4 Manufacturing 4
( S )-( 3- nitrofenvlIpentansvre ( XXIV\ ( S )-( 3-nitrophenylpentanoic acid ( XXIV\
(S)-dimetyl-l-[l-(3-nitrofenyl)propyl]malonat (XXIII, fremstilling 3, 0,73 g, 2,26 mmol) tilbakeløpskokes i saltsyre (6 N, 10 ml) i 18 timer. Reaksjonsblandingen avkjøles og ekstraheres med etylacetat. Etylacetatfasen vaskes med vann, separeres og kondenseres for å gi tittelforbindelsen, [a]o = 13,3° (metanol, c = 1); TLC (kiselgel GF, eddiksyre/etylacetat/heksan, 2/20/80), Rf = 0,46; NMR (CDC13, TMS) 0,78-0,83, 1,59-1,82, 2,59-2,78, 3,07-3,17, 7,44-7,54 og 8,04-8,10 8. (S)-Dimethyl-1-[1-(3-nitrophenyl)propyl]malonate (XXIII, Preparation 3, 0.73 g, 2.26 mmol) is refluxed in hydrochloric acid (6 N, 10 mL) for 18 h. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phase is washed with water, separated and condensed to give the title compound, [α]o = 13.3° (methanol, c = 1); TLC (silica gel GF, acetic acid/ethyl acetate/hexane, 2/20/80), Rf = 0.46; NMR (CDCl 3 , TMS) 0.78-0.83, 1.59-1.82, 2.59-2.78, 3.07-3.17, 7.44-7.54 and 8.04- 8,10 8.
Fremstilling 5 Manufacturing 5
f±)- 3-( 3- nitrofenyl) pentansyremetvlester fxi11\ f±)- 3-( 3- nitrophenyl)pentanoic acid methyl ester fxi11\
Til en oppløsning av (±)-3-(3-nitrofenyl)pentansyre (XXIV, 30,21 g, 135 mmol) i metanol (250 ml) tilsettes konsentrert svovelsyre (0,6 ml). Den resulterende blanding tilbakeløpskokes i 3 timer. Ved avkjøling deles blandingen mellom etylacetat og natriumbikarbonat (5 % vandig). Det vandige lag separeres og tilbakeekstraheres med to ytterligere porsjoner av etylacetat. De kombinerte organiske faser vaskes med mettet, vandig natriumklorid, tørkes over natriumsulfat, filtreres og konsentreres for a gi tittelforbindelsen, TLC (kiselgel GF) for eddiksyre/etylacetat/heksan (2/20/80), Rf = 0,54, for etylacetat/heksan (20/80), Rf = 0,54; NMR (CDC13, TMS) 0,80, 1,56-1,83, 2,55-2,75, 3,05-3,2, 3,57, 7,4-7,55 og 8,03-8,12 6. To a solution of (±)-3-(3-nitrophenyl)pentanoic acid (XXIV, 30.21 g, 135 mmol) in methanol (250 ml) is added concentrated sulfuric acid (0.6 ml). The resulting mixture is refluxed for 3 hours. On cooling, the mixture is partitioned between ethyl acetate and sodium bicarbonate (5% aqueous). The aqueous layer is separated and back-extracted with two further portions of ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to give the title compound, TLC (silica gel GF) for acetic acid/ethyl acetate/hexane (2/20/80), Rf = 0.54, for ethyl acetate /hexane (20/80), Rf = 0.54; NMR (CDCl 3 , TMS) 0.80, 1.56-1.83, 2.55-2.75, 3.05-3.2, 3.57, 7.4-7.55 and 8.03- 8.12 6.
Fremstilling 6 Production 6
( S\- 3-( 3- nitrofenyl^ pentansyremetylester fXIII> ( S\- 3-( 3- nitrophenyl^ pentanoic acid methyl ester fXIII>).
Ved å følge den generelle prosedyre ifølge fremstilling 5 og ved å gjøre ikke-kritiske variasjoner, men med start med (S)-3-(3-nitrofenyl)pentansyre (XXIV, fremstilling 4), oppnås tittelforbindelsen. Following the general procedure of Preparation 5 and making non-critical variations, but starting with (S)-3-(3-nitrophenyl)pentanoic acid (XXIV, Preparation 4), the title compound is obtained.
Eksempel 1 Example 1
Etvl- 3- hvdroksv- 3-( 2- fenvletvlIheksanoat t II) Ethyl- 3- hydroxy- 3-( 2- phenylethyl hexanoate t II)
Til en oppløsning av diisopropylamin (32,2 ml, To a solution of diisopropylamine (32.2 ml,
230 mmol) i tetrahydrofuran (240 ml) ved -58 °C tilsettes 2,63 M n-butyllitium i heksan (87,4 ml, 230 mmol) i løpet av 230 mmol) in tetrahydrofuran (240 ml) at -58 °C is added 2.63 M n-butyllithium in hexane (87.4 ml, 230 mmol) during
1 time. Etylacetat (21,4 ml, 220 mmol) tilsettes deretter, og reaksjonsblandingen omrøres i 1 time under avkjøling til 1 hour. Ethyl acetate (21.4 mL, 220 mmol) is then added and the reaction mixture is stirred for 1 h while cooling to
-70 °C. l-fenyl-3-heksanon (I, 35,2 g, 200 mmol) tilsettes langsomt i løpet av 30 minutter, og reaksjonsblandingen omrøres i 1 time. Reaksjonen stanses med vandig ammoniumklorid (100 ml), og reaksjonsblandingen oppvarmes til 20-25 °C. Blandingen surgjøres deretter med saltsyre (4 M). Det ønskede produkt ekstraheres med metyl-t-butyleter, tørkes over magnesiumsulfat og konsentreres for å gi tittelforbindelsen, TLC, Rf = 0,71 (etylacetat/heksan, 30/70); NMR (CDC13) 7,28-7,12, 4,13, 3,60, 2,73-2,63, 2,50, 1,83-1,77, 1,58-1,53, 1,41-1,36, 1,24 og 0,93 8; CMR (CDCI3) 173,0, 143,2, 128,5, 128,4, 128,3, 128,1, 125,8, 72,8, 60,6, 42,9, 41,3, 30,1, 17,0, 14,6 og 14,2 5; MS (CI, ammoniakk) m/z (relativ intensitet) 282 -70 °C. 1-Phenyl-3-hexanone (I, 35.2 g, 200 mmol) is added slowly over 30 minutes, and the reaction mixture is stirred for 1 hour. The reaction is stopped with aqueous ammonium chloride (100 ml), and the reaction mixture is heated to 20-25 °C. The mixture is then acidified with hydrochloric acid (4 M). The desired product is extracted with methyl t-butyl ether, dried over magnesium sulfate and concentrated to give the title compound, TLC, Rf = 0.71 (ethyl acetate/hexane, 30/70); NMR (CDCl 3 ) 7.28-7.12, 4.13, 3.60, 2.73-2.63, 2.50, 1.83-1.77, 1.58-1.53, 1, 41-1.36, 1.24 and 0.93 8; CMR (CDCI3) 173.0, 143.2, 128.5, 128.4, 128.3, 128.1, 125.8, 72.8, 60.6, 42.9, 41.3, 30, 1, 17.0, 14.6 and 14.2 5; MS (CI, ammonia) m/z (relative intensity) 282
(100), 264 (63), 247 (10), 194 (13), 172 (5), 159 (5). (100), 264 (63), 247 (10), 194 (13), 172 (5), 159 (5).
Eksempel 2 Example 2
3- hydroksy- 3-( 2- fenyletyl) heksansyre ( 111 ) 3- hydroxy- 3-( 2- phenylethyl) hexanoic acid ( 111 )
Etyl-3-hydroksy-3-(2-fenletyl)heksanoate (II, eksempel 1, 200 mmol) oppløses i metanol (423 ml), og 2 M natriumhydroksid (150 ml, 300 mmol) tilsettes. Reaksjonsblandingen omrøres ved 20-25 °C over natten. Metanolen fjernes, og den resterende vandige blanding surgjøres med saltsyre (4 M). Det ønskede produkt ekstraheres med metyl-t-butyleter og tørkes over magnesium sulfat. Produktet konsentreres for å gi tittelforbindelsen, TLC, Rf = 0,10 (etylacetat/heksan, 30/70); NMR (CDC13) 7,43-7,13, 2,77-2,62, 2,06, 1,87-1,76, 1,63-1,57, 1,45-1,31 og 0,93 8; CMR (CDCI3) 176,9, 141,9, 128,4, 128,3, 125,9, 73,4, 42,7, 41,4, 40,9, 31,9, 17,0 og 14,5 8; MS (CI, ammoniakk) m/z (relativ intensitet) 254 (100), 236 (28), 218 (3), 194 (3), 159 (5). Ethyl 3-hydroxy-3-(2-phenethyl)hexanoate (II, Example 1, 200 mmol) is dissolved in methanol (423 mL), and 2 M sodium hydroxide (150 mL, 300 mmol) is added. The reaction mixture is stirred at 20-25 °C overnight. The methanol is removed, and the remaining aqueous mixture is acidified with hydrochloric acid (4 M). The desired product is extracted with methyl-t-butyl ether and dried over magnesium sulfate. The product is concentrated to give the title compound, TLC, Rf = 0.10 (ethyl acetate/hexane, 30/70); NMR (CDCl 3 ) 7.43-7.13, 2.77-2.62, 2.06, 1.87-1.76, 1.63-1.57, 1.45-1.31 and 0, 93 8; CMR (CDCI3) 176.9, 141.9, 128.4, 128.3, 125.9, 73.4, 42.7, 41.4, 40.9, 31.9, 17.0 and 14, 5 8; MS (Cl, ammonia) m/z (relative intensity) 254 (100), 236 (28), 218 (3), 194 (3), 159 (5).
Eksempel 3 Example 3
( R)- 3- hydroksy- 3-( 2- fenyletyl^ heksansyre. i lR. 2S^- norefedrin-salt ( IV) ( R)- 3- hydroxy- 3-( 2- phenylethyl^ hexanoic acid. in lR. 2S^- norephedrine salt ( IV)
3-hydroksy-3-{2-fenyletyl)heksansyre (III, eksempel 2, 2,83 g, 11,97 mmol, justert for metyl-t-butyleter) oppløses i acetonitril (15 ml). (IR,2S)-norefedrin (910 mg, 5,99 mmol, 0,5 ekv.) tilsettes, og blandingen omrøres over natten ved 20-25 °C. Etter ca. 1 time begynner produktet å utfelles. Morgenen etter avkjøles oppsiemmingen til 0 °C i 1 time før filtrering for å oppsamle hydroksysyresaltet. Filterkaken vaskes med acetonitril (9 ml, kald) og tørkes under redusert trykk og med varme for å gi det ønskede produkt. 3-Hydroxy-3-{2-phenylethyl)hexanoic acid (III, Example 2, 2.83 g, 11.97 mmol, adjusted for methyl-t-butyl ether) is dissolved in acetonitrile (15 mL). (IR,2S)-norephedrine (910 mg, 5.99 mmol, 0.5 equiv) is added and the mixture is stirred overnight at 20-25 °C. After approx. After 1 hour, the product begins to precipitate. The following morning, the slurry is cooled to 0 °C for 1 hour before filtering to collect the hydroxy acid salt. The filter cake is washed with acetonitrile (9 ml, cold) and dried under reduced pressure and with heat to give the desired product.
Dette materialet (ca. 1,5 g) oppslemmes i acetonitril (21 ml) og oppvarmes til 70 °C i 30 minutter. Den resulterende løsning avkjøles gradvis til 20-25 °C når produktet utfelles. Etter 2 timer ved 20-25 °C oppsamles produktet ved vakuumfiltrering, vaskes med acetonitril (21 ml) og tørkes ved 20-25 °C under redusert trykk. This material (approx. 1.5 g) is suspended in acetonitrile (21 ml) and heated to 70 °C for 30 minutes. The resulting solution is gradually cooled to 20-25 °C as the product precipitates. After 2 hours at 20-25 °C, the product is collected by vacuum filtration, washed with acetonitrile (21 ml) and dried at 20-25 °C under reduced pressure.
Dette materialet oppslemmes på nytt i acetonitril This material is resuspended in acetonitrile
(21 ml) og oppvarmes ved 70 °C i 30 minutter. Den resulterende løsning avkjøles gradvis til romtemperatur, 20-25 °C, når produktet utfelles. Etter 2 timer ved 20-25 °C oppsamles produktet ved vakuumfiltrering, vaskes med acetonitril (21 ml) (21 ml) and heated at 70 °C for 30 minutes. The resulting solution is gradually cooled to room temperature, 20-25 °C, when the product precipitates. After 2 hours at 20-25 °C, the product is collected by vacuum filtration, washed with acetonitrile (21 ml)
og tørkes ved 20-25 °C under redusert trykk for å gi tittelforbindelsen, smp. « 113-117 °C; NMR (metanol) 7,41-7,08, 5,18, 4,98, 3,15, 2,65-2,60, 2,34, 1,79-1,73, 1,56-1,52, 1,43-1,37, 1,06 og 0,92 5; CMR (metanol) 181,4, 144,6, 142,2, 130,2-129,3, 127,6, 127,1, 74,5, 73,9, 54,0, 46,4, 43,6, 43,4, 31,9, 31,9, 18,6, 15,7 og 12,9 8; MS (CI, ammoniakk) m/z (relativ intensitet) 388 (25), 303 (15), 254 (30), 236 (7), 152 (100); [«]£ = 16 (C = 1,0, metanol). and dried at 20-25 °C under reduced pressure to give the title compound, m.p. « 113-117 °C; NMR (methanol) 7.41-7.08, 5.18, 4.98, 3.15, 2.65-2.60, 2.34, 1.79-1.73, 1.56-1, 52, 1.43-1.37, 1.06 and 0.925; CMR (methanol) 181.4, 144.6, 142.2, 130.2-129.3, 127.6, 127.1, 74.5, 73.9, 54.0, 46.4, 43, 6, 43.4, 31.9, 31.9, 18.6, 15.7 and 12.9 8; MS (CI, ammonia) m/z (relative intensity) 388 (25), 303 (15), 254 (30), 236 (7), 152 (100); [«]£ = 16 (C = 1.0, methanol).
Eksempel 4 Example 4
( 6R)- 5. 6- dihvdro- 4- hvdroksv- 6- f 1- f 2- fenvl) etvl1- 6- propvl- 2H-pvran- 2- on ( VI) ( 6R)- 5. 6- dihvdro- 4- hvdroksv- 6- f 1- f 2- phenvl) etvl1- 6- propvl- 2H- pvran- 2- one ( VI)
(R)-3-hydroksy-3-(2-fenyletyl)heksansyre, (IR,2S)-norefedrinsalt (IV, eksempel 3, 81 g, 209 mmol) omdannes til den frie syre, (R)-3-hydroksy-3-(2-fenyletyl)heksansyre ved oppslemming av saltet i etylacetat (810 ml) og tilsetning av saltsyre (IM, 810 ml). Den frie syre ekstraheres med etylacetat, og etylacetatlaget oppsamles og konsentreres til en olje. Den frie syre oppløses deretter på nytt i tetrahydrofuran (490 ml), og løsningen avkjøles til -10 °C. Karbonyldiimidazol (37,3 g, 230 mmol) tilsettes, og reaksjonsblandingen omrøres kaldt i 2 timer. Monoetylmalonatmagnesiumsalt (65,9 g, 230 mmol) tilsettes, og reaksjonsblandingen oppvarmes gradvis til 20-25 °C under omrøring over natten. Reaksjonen stanses med saltsyre (1 M, 490 ml), og det organiske lag oppsamles. Det organiske lag vaskes med en natriumbikarbonat-løsning og konsentreres til 294 ml inneholdende (R)-etyl-S-hydroksy-7-fenyl-5-propylheptanoat (V). En løsning av natriumhydroksid (0,5 M, 460 ml, 230 mmol) tilsettes til den konsen-trerte løsning, og den resulterende tåkete blanding omrøres ved 20-25 °C over natten. Metyl-t-butyleter tilsettes, og det vandige lag oppsamles. Den vandige fase surgjøres med saltsyre (4 M), og produktet ekstraheres med metyl-t-butyleter. Metyl-t-butyleter laget tørkes over natriumsulfat og konsentreres for å gi tittelforbindelsen, TLC, Rf = 0,22 (etylacetat/heksan, 50/50); NMR (CDC13) 7,29-7,13, 3,39, 2,70, 2,71-2,62, 1,98-1,93, 1,74-1,66, 1,45-1,34 og 0,93 8; CMR (CDC13) 176,89, 167,5, 140,4, 128,6, 128,4, 128,2, 128,2, 126,3, 83,2, 60,1, (R)-3-Hydroxy-3-(2-phenylethyl)hexanoic acid, (IR,2S)-norephedrine salt (IV, Example 3, 81 g, 209 mmol) is converted to the free acid, (R)-3-hydroxy- 3-(2-phenylethyl)hexanoic acid by slurrying the salt in ethyl acetate (810 ml) and adding hydrochloric acid (1M, 810 ml). The free acid is extracted with ethyl acetate, and the ethyl acetate layer is collected and concentrated to an oil. The free acid is then redissolved in tetrahydrofuran (490 ml), and the solution is cooled to -10 °C. Carbonyldiimidazole (37.3 g, 230 mmol) is added and the reaction mixture is stirred cold for 2 hours. Monoethylmalonate magnesium salt (65.9 g, 230 mmol) is added and the reaction mixture is gradually warmed to 20-25 °C with stirring overnight. The reaction is quenched with hydrochloric acid (1 M, 490 ml) and the organic layer is collected. The organic layer is washed with a sodium bicarbonate solution and concentrated to 294 ml containing (R)-ethyl-S-hydroxy-7-phenyl-5-propylheptanoate (V). A solution of sodium hydroxide (0.5 M, 460 mL, 230 mmol) is added to the concentrated solution and the resulting cloudy mixture is stirred at 20-25 °C overnight. Methyl t-butyl ether is added and the aqueous layer is collected. The aqueous phase is acidified with hydrochloric acid (4 M), and the product is extracted with methyl-t-butyl ether. The methyl t-butyl ether layer is dried over sodium sulfate and concentrated to give the title compound, TLC, Rf = 0.22 (ethyl acetate/hexane, 50/50); NMR (CDCl 3 ) 7.29-7.13, 3.39, 2.70, 2.71-2.62, 1.98-1.93, 1.74-1.66, 1.45-1, 34 and 0.93 8; CMR (CDC13) 176.89, 167.5, 140.4, 128.6, 128.4, 128.2, 128.2, 126.3, 83.2, 60.1,
47,1, 44,3, 40,7, 40,4, 29,6, 16,8 og 14,5 8; MS (CI, ammoniakk) m/z (relativ intensitet) 278 (100), 254 (15), 236 (15), 217 (5), 195 (5), 159 (3). 47.1, 44.3, 40.7, 40.4, 29.6, 16.8 and 14.5 8; MS (Cl, ammonia) m/z (relative intensity) 278 (100), 254 (15), 236 (15), 217 (5), 195 (5), 159 (3).
Eksempel 5 Example 5
M- fenylfenoksyl ( 4- klortiofenoksylmetan ( vim M- phenylphenoxyl ( 4- chlorothiophenoxylmethane ( vim
Til en oppsiemming av paraformaldehyd (36,24 g, For a sieving of paraformaldehyde (36.24 g,
1,21 mol, 1,58 ekv.) i toluen (243 ml) ved 22 °C tilsettes vandig hydrogenbromid (48,5 vekt%, 652 ml, 5,86 mol, 1.21 mol, 1.58 eq.) in toluene (243 ml) at 22 °C is added aqueous hydrogen bromide (48.5% by weight, 652 ml, 5.86 mol,
7,68 ekv.) med en endoterm til 18 °C. Den resulterende bi-fasiske løsning oppvarmes til 40 °C, og en løsning av 4-klortiofenol (VII, 138,81 g, 0,960 mol, 1,26 ekv.) i toluen (116 ml) tilsettes i løpet av en halv time under opprettholdelse av temperaturen på 40-43 °C, og skylles med toluen (50 ml). Blandingen oppvarmes deretter til 50 °C og omrøres i 1 time. Blandingen avkjøles til 10 °C, fasene separeres, og den vandige fase vaskes med toluen (250 ml). De kombinerte organiske faser behandles med isvann (500 ml), heksaner (350 ml), og fasene separeres. Den vandige fase vaskes deretter med toluen (200 ml), og de kombinerte organiske faser tørkes over magnesiumsulfat og konsentreres for å gi urenset brommetyltio-4-klorbenzen (268,01 g), NMR 7,43, 7,34, 4,79 8; CMR 134,37, 132,05, 131,78, 129,46, 37,32 8; HRMS (El<+>) beregnet for C7H6BrClS = 235,9063, funnet = 235,9063. 7.68 eq.) with an endotherm to 18 °C. The resulting biphasic solution is heated to 40 °C and a solution of 4-chlorothiophenol (VII, 138.81 g, 0.960 mol, 1.26 eq) in toluene (116 mL) is added over half an hour under maintaining the temperature at 40-43 °C, and rinsed with toluene (50 ml). The mixture is then heated to 50 °C and stirred for 1 hour. The mixture is cooled to 10 °C, the phases are separated, and the aqueous phase is washed with toluene (250 ml). The combined organic phases are treated with ice water (500 mL), hexanes (350 mL), and the phases are separated. The aqueous phase is then washed with toluene (200 mL), and the combined organic phases are dried over magnesium sulfate and concentrated to give crude bromomethylthio-4-chlorobenzene (268.01 g), NMR 7.43, 7.34, 4.79 8; CMR 134.37, 132.05, 131.78, 129.46, 37.32 8; HRMS (El<+>) calcd for C7H6BrClS = 235.9063, found = 235.9063.
Til en oppløsning av 4-fenylfenol (129,91 g, To a solution of 4-phenylphenol (129.91 g,
0,763 mol, 1,00 ekv.) i DMF (400 ml) ved -10 °C tilsettes en oppløsning av kalium-t-butoksid i THF (20 vekt%, 429,40 g, 0,765 mol, 1,00 ekv.), etterfulgt av THF (50 ml), under opprettholdelse av temperaturen lavere enn 5 °C. Blandingen konsentreres til 557 g nettovekt, og DMF (33 ml) tilsettes etterfulgt av urenset brommetyltio-4-klorbenzen, fremstilt ovenfor, med en fri eksoterm fra 22 til 70 ''C. Det urensede brommetyltio-4-klorbenzen skylles med DMF (50 ml), og den resulterende oppslemming omrøres ved 80 °C i 1/2 time. Blandingen avkjøles til 22 °C, og heksaner (400 ml) etterfulgt av vann (500 ml) tilsettes. Bunnfallet oppsamles ved vakuumfiltrering og vaskes med vann (1500 ml) og metanol (300 ml) og tørkes i en nitrogenstrøm for å gi et fast materiale (251,25 g). Det faste materialet oppløses i metylenklorid 0.763 mol, 1.00 eq.) in DMF (400 mL) at -10 °C is added a solution of potassium t-butoxide in THF (20 wt%, 429.40 g, 0.765 mol, 1.00 eq.) , followed by THF (50 mL), maintaining the temperature below 5 °C. The mixture is concentrated to 557 g net weight and DMF (33 ml) is added followed by crude bromomethylthio-4-chlorobenzene, prepared above, with a free exotherm from 22 to 70 °C. The crude bromomethylthio-4-chlorobenzene is rinsed with DMF (50 mL) and the resulting slurry is stirred at 80 °C for 1/2 hour. The mixture is cooled to 22 °C and hexanes (400 mL) followed by water (500 mL) are added. The precipitate is collected by vacuum filtration and washed with water (1500 ml) and methanol (300 ml) and dried in a stream of nitrogen to give a solid (251.25 g). The solid material is dissolved in methylene chloride
(1 1) og tørkes over magnesiumsulfat og vaskes med metylenklorid {200 ml). En konsentrering ved konstant volum (1300-1800 ml) utføres deretter under tilsetning av totalt 1,35 1 metanol og med sluttresultatet 1344 g nettovekt. Det resulterende bunnfall oppsamles ved 20-25 °C ved vakuumfiltrering, vaskes med metanol (1 1) og tørkes ved 65 °C under redusert trykk for å gi tittelforbindelsen, smp. = 99-101 °C; TLC (Rf 0,64, etylacetat/heksaner, 1/9); HPLC (rt) = 9,67 min.; NMR (CDCl3) 7,55-6,99 og 5,44 8; CMR (CDC13) 155,99, 140,52, 135,28, 133,48, 132,06, 129,18, 128,75, 128,24, 126,90, 126,80, 116,34, 73,15 8; MS (Cl, NH3) m/z (relativ intensitet) 346 (1,7), 344 (3,5), 328 (3,8), 326 (8,1), 201 (11), 200 (1 1) and dried over magnesium sulfate and washed with methylene chloride {200 ml). A concentration at constant volume (1300-1800 ml) is then carried out with the addition of a total of 1.35 1 methanol and with the final result 1344 g net weight. The resulting precipitate is collected at 20-25 °C by vacuum filtration, washed with methanol (1 L) and dried at 65 °C under reduced pressure to give the title compound, m.p. = 99-101 °C; TLC (Rf 0.64, ethyl acetate/hexanes, 1/9); HPLC (rt) = 9.67 min.; NMR (CDCl 3 ) 7.55-6.99 and 5.44 8; CMR (CDC13) 155.99, 140.52, 135.28, 133.48, 132.06, 129.18, 128.75, 128.24, 126.90, 126.80, 116.34, 73, 15 8; MS (Cl, NH3) m/z (relative intensity) 346 (1.7), 344 (3.5), 328 (3.8), 326 (8.1), 201 (11), 200
(100). (100).
Eksempel 6 Example 6
l- klormetoksy- 4- fenvlbenzen ( IX) l-chloromethoxy-4-phenylbenzene (IX)
Til en blanding av (4-fenylfenoksy)(4-klortio-fenoksy)metan (VIII, eksempel 5, 176,45 g, 539,9 mmol) i metylenklorid (750 ml) ved 21 °C tilsettes en oppløsning av sulfurylklorid (73,32 g, 543,2 mmol, 1,01 ekv.) i metylenklorid (150 ml) ved opprettholdelse av temperaturen under 23 °C i 8 minutter. Blandingen omrøres ved 20 °C i 11 minutter og avkjøles deretter til 3 °C. En blanding av sykloheksen A solution of sulfuryl chloride (73 .32 g, 543.2 mmol, 1.01 eq.) in methylene chloride (150 mL) while maintaining the temperature below 23 °C for 8 min. The mixture is stirred at 20°C for 11 minutes and then cooled to 3°C. A mixture of the cyclowitch
(60,7 ml, 599 mmol, 1,11 ekv.) i metylenklorid (100 ml) tilsettes i løpet av 10 minutter ved 3-5 °C, oppvarmes deretter til 19 °C og omrøres i 10 minutter. Blandingen konsentreres til 600 ml totalvolum, og heksaner (500 ml) tilsettes. Blandingen konsentreres til 500 ml, og heksaner (300 ml) tilsettes. Den resulterende oppslemming konsentreres til 500 ml, og pentan (1,3 1) tilsettes. Oppslemmingen avkjøles til -50 °C, og bunnfallet oppsamles ved vakuumfiltrering og vaskes med pentan (700 ml) ved -30 °C og tørkes for å gi et fast materiale (115,28 g). En porsjon (110,34 g) av det faste materialet oppløses i metylenklorid (200 ml). Heksaner (1 1) tilsettes, og blandingen konsentreres til 949 g. Heksan (200 ml) tilsettes, og blandingen konsentreres til 589 g. Heksan (500 ml) tilsettes, oppslemmingen avkjøles til -30 °C, bunnfallet oppsamles ved vakuumfiltrering, vaskes med heksan (300 ml) og tørkes for å gi tittelforbindelsen, smp. 67-70 °C; TLC, Rf = (60.7 mL, 599 mmol, 1.11 eq.) in methylene chloride (100 mL) is added over 10 min at 3-5 °C, then warmed to 19 °C and stirred for 10 min. The mixture is concentrated to 600 ml total volume, and hexanes (500 ml) are added. The mixture is concentrated to 500 mL, and hexanes (300 mL) are added. The resulting slurry is concentrated to 500 mL and pentane (1.3 L) is added. The slurry is cooled to -50 °C and the precipitate is collected by vacuum filtration and washed with pentane (700 mL) at -30 °C and dried to give a solid (115.28 g). A portion (110.34 g) of the solid material is dissolved in methylene chloride (200 ml). Hexanes (1 L) are added and the mixture is concentrated to 949 g. Hexane (200 ml) is added and the mixture is concentrated to 589 g. Hexane (500 ml) is added, the slurry is cooled to -30 °C, the precipitate is collected by vacuum filtration, washed with hexane (300 mL) and dried to give the title compound, m.p. 67-70 °C; TLC, R f =
0,68 (etylacetat/heksaner, 8/92); HPLC rt = 6,45 min.; NMR 7,80-7,13 og 5,89 6; CMR <CDC13) 155,03, 140,34, 136,49, 128,78, 128,35, 127,10, 126,88, 116,39 og 77,16 5; HRMS (EI<+>) beregnet for C13HnC10 = 218,0498, funnet - 218,0493. 0.68 (ethyl acetate/hexanes, 8/92); HPLC rt = 6.45 min.; NMR 7.80-7.13 and 5.89 6; CMR < CDCl3 ) 155.03, 140.34, 136.49, 128.78, 128.35, 127.10, 126.88, 116.39 and 77.16 5; HRMS (EI<+>) calculated for C13HnC10 = 218.0498, found - 218.0493.
Eksempel 7 Example 7
( R)- i 4- fenvlfenoksv) metvl- 3- f 2- fenvletvl\- 3- f( 4- fenvlfenoksv)-metoksy1heksanoat ( X) ( R )- i 4- phenylphenoxy) methyl- 3- f 2- phenylphenoxy)- 3- f( 4- phenylphenoxy)- methoxylhexanoate ( X)
Til en oppslemming av (R)-3-hydroksy-3-(2-fenyletyl)-heksansyre-(-)-norefedrinsalt (IV, eksempel 4, 25,04 g, To a slurry of (R)-3-hydroxy-3-(2-phenylethyl)-hexanoic acid-(-)-norephedrine salt (IV, Example 4, 25.04 g,
64,62 mmol) i vann (185 ml) og MTBE (185 ml) ved 20-25 °C tilsettes vandig saltsyre (37,5 vekt%, 7,51 g, 77,24 mmol, 64.62 mmol) in water (185 ml) and MTBE (185 ml) at 20-25 °C is added aqueous hydrochloric acid (37.5% by weight, 7.51 g, 77.24 mmol,
1,20 ekv.), som justerer pH fra 8,04 til 1,30. Fasene separeres, og den vandige fase vaskes med MTBE (185 ml). De organiske faser tørkes over magnesiumsulfat og konsentreres. Til konsentratet tilsettes deretter toluen (77 ml), N,N-diisopropyletylamin (96 ml, 551 mmol, 8,53 ekv.) og 1-klormetoksy-4-fenylbenzen (IX eksempel 6, 71,88 g, 328,68 mmol, 5,09 ekv). Blandingen oppvarmes deretter til 110 °C og omrøres ved 110-117 "C i 5 timer. Blandingen avkjøles til 65 °C, og metanol (800 ml) tilsettes. Den resulterende oppslemming avkjøles til 1.20 eq.), which adjusts the pH from 8.04 to 1.30. The phases are separated, and the aqueous phase is washed with MTBE (185 ml). The organic phases are dried over magnesium sulfate and concentrated. To the concentrate are then added toluene (77 ml), N,N-diisopropylethylamine (96 ml, 551 mmol, 8.53 eq.) and 1-chloromethoxy-4-phenylbenzene (IX Example 6, 71.88 g, 328.68 mmol , 5.09 eq). The mixture is then heated to 110 °C and stirred at 110-117 °C for 5 hours. The mixture is cooled to 65 °C and methanol (800 mL) is added. The resulting slurry is cooled to
-30 °C, og produktet oppsamles ved vakuumfiltrering, vaskes med metanol (200 ml) og tørkes for a gi et råprodukt. En analytisk prøve oppnås ved kromatografi etylacetat/heksaner), etterfulgt av krystallisering for å gi tittelforbindelsen, smp. = 104,0-105,5 °C; TLC, Rf = 0,50 (15% etylacetat/heksaner); HPLC rt « 13,8 min.; NMR (CDC13) 7,51-7,04, 5,78, 5,32, 2,75, 2,64-2,58, 2,03-1,97, 1,78-1,72, 1,41-1,28 og 0,86 6; CMR (CDC13) 169,38, 157,14, 156,14, 142,04, 140,71, 140,41, 135,85, 134,56, 128,75, 128,68, 128,35, 128,29, 128,09, 126,97, 126,81, 126,73, 125,78, 116,13, 87,34, 85,20, 80,40, 41,19, 38,80, 38,61, 29,73, 16,74, 14,35 5; MS (CI, NH3) m/z (relativ intensitet) 620 (1,7), 619 (7,8), 618 (19), 418 (13), 266 -30 °C, and the product is collected by vacuum filtration, washed with methanol (200 ml) and dried to give a crude product. An analytical sample is obtained by chromatography (ethyl acetate/hexanes), followed by crystallization to give the title compound, m.p. = 104.0-105.5 °C; TLC, Rf = 0.50 (15% ethyl acetate/hexanes); HPLC rt « 13.8 min.; NMR (CDCl 3 ) 7.51-7.04, 5.78, 5.32, 2.75, 2.64-2.58, 2.03-1.97, 1.78-1.72, 1, 41-1.28 and 0.86 6; CMR (CDC13) 169.38, 157.14, 156.14, 142.04, 140.71, 140.41, 135.85, 134.56, 128.75, 128.68, 128.35, 128, 29, 128.09, 126.97, 126.81, 126.73, 125.78, 116.13, 87.34, 85.20, 80.40, 41.19, 38.80, 38.61, 29.73, 16.74, 14.35 5; MS (Cl, NH3) m/z (relative intensity) 620 (1.7), 619 (7.8), 618 (19), 418 (13), 266
(100); [ a]% = -4 (C = 1,0, metylenklorid). (100); [ a]% = -4 (C = 1.0, methylene chloride).
Eksempel 8 Example 8
( R)- 3-( 2- fenvletvl)- 3- r f4- fenvlfenoksv) metoksv 1 heksanol ( XI) ( R )- 3-( 2- phenylethyl)- 3- r f4- phenylphenoxy) methoxy 1 hexanol ( XI)
Til en oppslemming av urenset (R-)-(4-fenylfenoksy)-metyl-3-(2-fenyletyl)-3-[(4-fenylfenoksy)metoksy]heksanoat (X, eksempel 7, 56,5 vekt%, 49,32 g, 46,38 mmol i toluen (500 ml) tilsettes en oppløsning av diisobutylaluminiumhydrid i toluen (1,52 M, 85 ml, 129,2 mmol, 2,79 ekv.) under opprettholdelse av temperaturen ved -20 °C. Blandingen oppvarmes langsomt til 1 °C i løpet av 2,5 timer og omrøres deretter i 1/2 time. Aceton (8,0 ml, 108,5 mmol, 2,34 ekv.) tilsettes, og blandingen overføres med en kanyle ved 18 °C i en oppløsning av sitronsyremonohydrat (136 g, 647,2 mmol, 14,0 ekv.) i vann (433 ml) med kontrollert eksoterm til 28 °C og skylles med toluen (100 ml). Blandingen omrøres ved 20-25 °C i 1,5 time, og uoppløst materiale fjernes ved vakuumfiltrering og vask med toluen. Fasene separeres i filtratet, og den vandige fase vaskes med toluen (2 x 300 ml). De organiske faser tørkes over magnesiumsulfat og vaskes deretter med vandig natriumhydroksid (0,5 M, 2 x 500 ml). De organiske faser konsentreres til 137 g nettovekt, og metanol (250 ml) tilsettes. Den resulterende oppslemming konsentreres, og metanol (250 ml) tilsettes. Blandingen konsentreres på nytt, og metanol (250 ml) tilsettes. Oppslemmingen avkjøles til -60 °C, og det uoppløste materialet fjernes ved filtrering. Filtratet konsentreres til 60 g nettovekt, heksan (500 ml) tilsettes, og blandingen konsentrert til 22 g nettovekt. Heksan (500 ml) tilsettes, og blandingen konsentreres på nytt til 40 g nettovekt. Metylen-klorid (25 ml) tilsettes, etterfulgt av langsom tilsetning av heksan (500 ml) og pentan (250 ml) under avkjøling til -55 °C. Produktet oppsamles ved vakuumfiltrering, vaskes med pentan (200 ml) og tørkes i en nitrogenstrøm for å gi det ønskede produkt. En analytisk prøve oppnås ved kromatografi (etylacetat/heksan), etterfulgt av krystallisering (metylenklorid/ heksan) for å gi tittelforbindelsen, smp. - 49-53 °C; TLC, Rf = 0,14 (15 % etylacetat/heksan); HPLC rt = 9,18 min.; NMR (CDC13) 7,56-7,07, 5,36, 3,76-3,74, 2,63-2,58, 1,94-1,88, 1,70-1,65, 1,38-1,30, 0,93 8; CMR (CDCI3) 157,05, 142,25, 140,73, 134,68, 128,70, 128,42, 128,29, 128,21, 126,76, 125,85, 116,07, 87,05, 81,85, 58,89, 38,77, 38,60, 38,23, 29,90, 17,04, 14,62 8; MS (CI, NH3) m/z (relativ intensitet) 423 (2,3), 422 (9,9), 252 (100); [a]£ = 6 (C = 1,0, metylenklorid) . To a slurry of crude (R-)-(4-phenylphenoxy)-methyl-3-(2-phenylethyl)-3-[(4-phenylphenoxy)methoxy]hexanoate (X, Example 7, 56.5 wt%, 49 .32 g, 46.38 mmol in toluene (500 ml) is added a solution of diisobutylaluminum hydride in toluene (1.52 M, 85 ml, 129.2 mmol, 2.79 eq.) while maintaining the temperature at -20 °C . The mixture is slowly warmed to 1 °C over 2.5 h and then stirred for 1/2 h. Acetone (8.0 mL, 108.5 mmol, 2.34 equiv) is added and the mixture is transferred by cannula at 18 °C in a solution of citric acid monohydrate (136 g, 647.2 mmol, 14.0 equiv) in water (433 mL) with controlled exotherm to 28 °C and rinsed with toluene (100 mL).The mixture is stirred at 20 -25 °C for 1.5 hours, and undissolved material is removed by vacuum filtration and washing with toluene. The phases are separated in the filtrate, and the aqueous phase is washed with toluene (2 x 300 ml). The organic phases are dried over magnesium sulfate and then washed with aqueous sodium hydroxide (0.5 M, 2 x 500 ml) The organic phases is concentrated to 137 g net weight, and methanol (250 ml) is added. The resulting slurry is concentrated and methanol (250 mL) is added. The mixture is concentrated again and methanol (250 mL) is added. The slurry is cooled to -60 °C, and the undissolved material is removed by filtration. The filtrate is concentrated to 60 g net weight, hexane (500 ml) is added, and the mixture concentrated to 22 g net weight. Hexane (500 mL) is added and the mixture is concentrated again to 40 g net weight. Methylene chloride (25 mL) is added, followed by slow addition of hexane (500 mL) and pentane (250 mL) while cooling to -55 °C. The product is collected by vacuum filtration, washed with pentane (200 ml) and dried in a stream of nitrogen to give the desired product. An analytical sample is obtained by chromatography (ethyl acetate/hexane), followed by crystallization (methylene chloride/hexane) to give the title compound, m.p. - 49-53 °C; TLC, Rf = 0.14 (15% ethyl acetate/hexane); HPLC rt = 9.18 min.; NMR (CDCl 3 ) 7.56-7.07, 5.36, 3.76-3.74, 2.63-2.58, 1.94-1.88, 1.70-1.65, 1, 38-1.30, 0.93 8; CMR (CDCI3) 157.05, 142.25, 140.73, 134.68, 128.70, 128.42, 128.29, 128.21, 126.76, 125.85, 116.07, 87, 05, 81.85, 58.89, 38.77, 38.60, 38.23, 29.90, 17.04, 14.62 8; MS (Cl, NH 3 ) m/z (relative intensity) 423 (2.3), 422 (9.9), 252 (100); [a]£ = 6 (C = 1.0, methylene chloride) .
Eksempel 9 Example 9
( R \- 3 -( 2- fenyletyl)- 3- r( 4- fenvlfenoksyImetoksy1heksanal fXII) ( R \- 3 -( 2- phenylethyl)- 3- r( 4- phenylphenoxyImethoxy1hexanal fXII)
Til en blanding av urenset (R)-3-(2-fenyletyl)-3-[(4-fenylfenoksy)metoksy]heksanol (XI, eksempel 8, 91,1 vekt%, 15,40 g, 34,68 mmol) i metylenklorid (47 ml) ved 0 °C tilsettes en løsning av kaliumbromid (0,4057 g, 3,409 mmol, 0,098 ekv.) og natriumbikarbonat (1,557 g, 18,53 mmol, 0,53 ekv.) i vann (20,5 ml), etterfulgt av 4-hydroksy-2,2,6,6-tetrametylpiperi-dinyloksy, fritt radikal (0,3060 g, 1,776 mmol, 0,051 ekv.). Vandig natriumhypokloritt (13,4 % (vekt/volum, 26,6 ml, To a mixture of crude (R)-3-(2-phenylethyl)-3-[(4-phenylphenoxy)methoxy]hexanol (XI, Example 8, 91.1 wt%, 15.40 g, 34.68 mmol) in methylene chloride (47 mL) at 0 °C is added a solution of potassium bromide (0.4057 g, 3.409 mmol, 0.098 eq.) and sodium bicarbonate (1.557 g, 18.53 mmol, 0.53 eq.) in water (20, 5 mL), followed by 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy, free radical (0.3060 g, 1.776 mmol, 0.051 equiv). Aqueous sodium hypochlorite (13.4% (w/v, 26.6 ml,
47,88 mmol, 1,38 ekv.) tilsettes deretter ved hjelp av en sprøytepumpe i løpet av 1 time under opprettholdelse av temperaturen ved 1-5 °C. En oppløsning av natriumtiosulfat-pentahydrat (0,5182 g, 2,088 mmol, 0,0602 ekv.) i vann (14 ml) tilsettes deretter. Fasene separeres ved 0 °C, og den vandige fase vaskes med 2 x 50 ml metylenklorid. De organiske faser filtreres umiddelbart gjennom magnesol (50,25 g) og gjennom-skylles med metylenklorid (400 ml). Ekstraktene konsentreres til en olje (30 g), og heksan (500 ml) tilsettes. Blandingen konsentreres til 250 g netto vekt, og heksan (100 ml) tilsettes. Blandingen konsentreres til 186 g nettovekt, og pentan (300 ml) tilsettes. Den resulterende oppslemming avkjøles til 47.88 mmol, 1.38 equiv.) is then added using a syringe pump over the course of 1 hour while maintaining the temperature at 1-5 °C. A solution of sodium thiosulfate pentahydrate (0.5182 g, 2.088 mmol, 0.0602 equiv) in water (14 mL) is then added. The phases are separated at 0 °C, and the aqueous phase is washed with 2 x 50 ml of methylene chloride. The organic phases are immediately filtered through magnesol (50.25 g) and rinsed through with methylene chloride (400 ml). The extracts are concentrated to an oil (30 g) and hexane (500 ml) is added. The mixture is concentrated to 250 g net weight, and hexane (100 ml) is added. The mixture is concentrated to 186 g net weight, and pentane (300 ml) is added. The resulting slurry is cooled to
-50 °C, og det ønskede produkt oppsamles ved vakuumfiltrering, vaskes ved -50 °C med pentan (100 ml) og tørkes for a gi en fast, analytisk ren tittelforbindelse, smp. = 47,0-48,5 °C; TLC, Rf = 0,41 (etylacetat/heksan, 10/90); HPLC rt = 10,95 min.; NMR (CDC13) 9,79, 7,53, 7,40, 7,26, 7,20-7,08, 5,40, 2,67, 2,65-2,56, 1,99, 1,76, 1,38, 0,93 5; CMR (CDC13) 201,83, 156,90, 141,69, 140,68, 134,82, 128,72, 128,47, 128,29, 128,24, 126,77, 125,99, 116,03, 87,19, 80,36, 50,14, 39,21, 39,14, 29,74, 16,86, 14,45 8; MS (CI, NH3) m/z (relativ intensitet) 420 (3,5), 220 (100); [a]£ = 14 (C = 1,0, metylenklorid) . Eksempel 10 ( 3S ) ( 7R)- 4- karbometoksy- 3-( 3- nitrofenyl)- T - t 2- fenyletyl)-7-ff4- fenvlfenokBy) metoksy1dekan- 5- ol fblandin<g> av diastereomerer ved C- 4 og C- 5) fXIV) Til en blanding av (S)-metyl-3-(3-nitrofenyl)-pentanoat, også kjent som (S)-3-(3-nitrofenyl)pentansyremetylester (XIII, fremstilling 6, 3,78 g, 15,932 mmol) i THF (55 ml) ved -80 °C tilsettes e oppløsning av natriumheksametyl-disilazid i THF (0,935 M, 17,5 ml, 16,36 mmol, 1,027 ekv.) i løpet av 7 minutter under opprettholdelse av temperaturen ved -80 til -85 °C. Den resulterende blanding oppvarmes deretter til -74 °C og omrøres ved -74 til -76 °C i 18 minutter. Blandingen avkjøles til -90 °C, og en oppløsning av (4R)-3-(2-fenyletyl)-3-[(4-fenylfenoksy)metoksy]heksanal (XII, eksempel 9, 6,50 g, 16,147 mmol, 1,013 ekv.) i THF tilsettes i løpet av 10 minutter under opprettholdelse av temperaturen ved -85 til -90 °C og skylles med THF (20 ml). Blandingen oppvarmes deretter til -71 °C, og mettet, vandig ammoniumkloridløsning -50 °C, and the desired product is collected by vacuum filtration, washed at -50 °C with pentane (100 ml) and dried to give a solid, analytically pure title compound, m.p. = 47.0-48.5 °C; TLC, Rf = 0.41 (ethyl acetate/hexane, 10/90); HPLC rt = 10.95 min.; NMR (CDCl 3 ) 9.79, 7.53, 7.40, 7.26, 7.20-7.08, 5.40, 2.67, 2.65-2.56, 1.99, 1, 76, 1.38, 0.93 5; CMR (CDC13) 201.83, 156.90, 141.69, 140.68, 134.82, 128.72, 128.47, 128.29, 128.24, 126.77, 125.99, 116, 03, 87.19, 80.36, 50.14, 39.21, 39.14, 29.74, 16.86, 14.45 8; MS (Cl, NH 3 ) m/z (relative intensity) 420 (3.5), 220 (100); [a]£ = 14 (C = 1.0, methylene chloride) . Example 10 ( 3S ) ( 7R )- 4- carbomethoxy- 3-( 3- nitrophenyl)- T - t 2- phenylethyl)-7-ff4- phenvlphenocBy) methoxyl decan- 5-ol fblandin<g> of diastereomers at C- 4 and C- 5) fXIV) To a mixture of (S)-methyl-3-(3-nitrophenyl)pentanoate, also known as (S)-3-(3-nitrophenyl)pentanoic acid methyl ester (XIII, Preparation 6, 3, 78 g, 15.932 mmol) in THF (55 ml) at -80 °C is added a solution of sodium hexamethyldisilazide in THF (0.935 M, 17.5 ml, 16.36 mmol, 1.027 equiv.) over 7 minutes under maintaining the temperature at -80 to -85 °C. The resulting mixture is then warmed to -74°C and stirred at -74 to -76°C for 18 minutes. The mixture is cooled to -90 °C, and a solution of (4R)-3-(2-phenylethyl)-3-[(4-phenylphenoxy)methoxy]hexanal (XII, Example 9, 6.50 g, 16.147 mmol, 1.013 equiv.) in THF is added over 10 minutes while maintaining the temperature at -85 to -90 °C and rinsed with THF (20 mL). The mixture is then heated to -71 °C, and saturated aqueous ammonium chloride solution
(90 ml) tilsettes, etterfulgt av vann (90 ml) og MTBE (90 ml), og blandingen oppvarmes til 20-25 °C. Fasene separeres, og den vandige fase vaskes med MTBE (90 ml). Ekstraktene tørkes over magnesiumsulfat og konsentreres til en olje. En analytisk prøve oppnås ved kromatografi (etylacetat/heksaner) for å gi tittelforbindelsen, TLC, Rf - 0,16, 0,24 (etylacetat/heksaner, 10/90); HPLC rt = 12,52, 12,68, 12,97 min.; MS (elektrospray, natriumacetat) m/z (relativ intensitet) 662,5 (100). (90 mL) is added, followed by water (90 mL) and MTBE (90 mL), and the mixture is heated to 20-25 °C. The phases are separated, and the aqueous phase is washed with MTBE (90 ml). The extracts are dried over magnesium sulfate and concentrated to an oil. An analytical sample is obtained by chromatography (ethyl acetate/hexanes) to give the title compound, TLC, Rf - 0.16, 0.24 (ethyl acetate/hexanes, 10/90); HPLC rt = 12.52, 12.68, 12.97 min.; MS (electrospray, sodium acetate) m/z (relative intensity) 662.5 (100).
Eksempel 11 Example 11
( 3S).( 7R)- 4- karbometoksv- 3-( 3- nitrofenvl)- 7-( 2- fenvletvl)- 7-f( 4- fenvlfenoksy) metoksy1dekan- 5- on ( blanding av diastereomerer ved C- 4) (3S)
En oppløsning av (3S),(7R)-4-karbometoksy-3-(3-nitro-feny1)-7-(2-fenyletyl)-7-[(4-fenylfenoksy)metoksy]dekan-5-ol (XIV, eksempel 10, 11,12 g, 79,0 vekt%, 13,73 mmol) i metylenklorid (530 ml) tilsettes til en oppmalt blanding av pyridin-klorkromat (16,099 g, 74,685 mmol, 5,44 ekv.), natriumacetat (6,984 g, 85,14 mmol, 6,20 ekv.) og florisil (5,181 g) under opprettholdelse av temperaturen lavere enn 11 °C. Blandingen oppvarmes til 21 °C og omrøres ved 20-25 °C i 20 timer. Den resulterende oppslemming filtreres gjennom magnesol (47,7 g) og skylles med metylenklorid (375 ml). Filtratet konsentreres til en olje. En analytisk prøve av tittelforbindelsen oppnås ved kromatografi (etylacetat/heksaner): TLC, Rf - 0,34 (etylacetat/heksaner, 10/90); HPLC rt = 13,02, 13,23 min.; NMR (CDC13) 8,05-8,01, 7,60-7,00, 5,37, 5,21, 4,03, 3,94, 3,75, 3,58-3,43, 3,39, 2,96, 2,78-1,37, 1,20, 0,91, 0,71-0,61 8; CMR (CDC13) 200,89, 200,60, 168,29, 167,81, 157,10, 157,05, 148,38, 148,30, 143,58, 143,32, 141,99, 141,93, 140,73, 140,69, 135,29, 135,01, 134,78, 129,38, 129,23, 128,75, 128,45, 128,36, 128,23, 126,77, 125,91, 125,80, 122,96, 122,80, 122,04, 122,00, 116,16, 87,14, 86,92, 80,93, 80,44, 66,34, 65,92, 52,79, 52,35, 49,02, 48,62, 46,28, 46,20, 38,70, 38,51, 38,43, 37,99, 30,10, 29,52, 26,92, 26,71, 16,64, 16,39, 14,39, 14,16, 11,81, 11,58; MS (CI, ammoniakk) m/z (relativ intensitet) 656 (2,8), 655 (6,1), 136 (100). A solution of (3S),(7R)-4-carbomethoxy-3-(3-nitro-phenyl)-7-(2-phenylethyl)-7-[(4-phenylphenoxy)methoxy]decan-5-ol (XIV , Example 10, 11.12 g, 79.0 wt%, 13.73 mmol) in methylene chloride (530 mL) is added to a ground mixture of pyridine-chlorochromate (16.099 g, 74.685 mmol, 5.44 eq.), sodium acetate (6.984 g, 85.14 mmol, 6.20 eq.) and florisil (5.181 g) while maintaining the temperature lower than 11 °C. The mixture is heated to 21 °C and stirred at 20-25 °C for 20 hours. The resulting slurry is filtered through magnesol (47.7 g) and rinsed with methylene chloride (375 mL). The filtrate is concentrated to an oil. An analytical sample of the title compound is obtained by chromatography (ethyl acetate/hexanes): TLC, Rf - 0.34 (ethyl acetate/hexanes, 10/90); HPLC rt = 13.02, 13.23 min.; NMR (CDCl 3 ) 8.05-8.01, 7.60-7.00, 5.37, 5.21, 4.03, 3.94, 3.75, 3.58-3.43, 3, 39, 2.96, 2.78-1.37, 1.20, 0.91, 0.71-0.61 8; CMR (CDC13) 200.89, 200.60, 168.29, 167.81, 157.10, 157.05, 148.38, 148.30, 143.58, 143.32, 141.99, 141, 93, 140.73, 140.69, 135.29, 135.01, 134.78, 129.38, 129.23, 128.75, 128.45, 128.36, 128.23, 126.77, 125.91, 125.80, 122.96, 122.80, 122.04, 122.00, 116.16, 87.14, 86.92, 80.93, 80.44, 66.34, 65, 92, 52.79, 52.35, 49.02, 48.62, 46.28, 46.20, 38.70, 38.51, 38.43, 37.99, 30.10, 29.52, 26.92, 26.71, 16.64, 16.39, 14.39, 14.16, 11.81, 11.58; MS (Cl, ammonia) m/z (relative intensity) 656 (2.8), 655 (6.1), 136 (100).
Eksempel 12 Example 12
( 3S).( 7R)- 4- karbometoksv- 7- hydroksy- 3- f3- nitrofenyl)- 7- f2-fenyletyHdekan- 5- on ( blanding av diastereomerer ved C- 4) f XVI) ( 3S).( 7R)- 4- carbomethoxyv- 7- hydroxy- 3- f3- nitrophenyl)- 7- f2-phenylethyHdecan- 5- one (mixture of diastereomers at C- 4) f XVI)
Til en blanding av (3S),(7R)-4-karbometoksy-3-(3-nitrofenyl)-7-(2-fenyletyl)-7-[(4-fenylfenoksy)metoksy]dekan-5-on (XV, eksempel 11, 9,14 g, 83,7 vekt%, 11,995 mmol) i THF (20 ml) ved 23 °C tilsettes en oppløsning av svovelsyre i metanol (0,524 M, 20 ml, 10,48 mmol, 0,87 ekv.). Blandingen hensettes ved 23 °C i 22 timer, og deretter tilsettes en opp-løsning av natriumbikarbonat (3,52 g, 41,90 mmol, 3,49 ekv.) i vann (50 ml), etterfulgt av MTBE (50 ml). Fasene separeres, og den vandige fase vaskes med MTBE (30 ml). De kombinerte organiske faser vaskes med vandig natriumhydroksid (0,5 M, 2 x 50 ml) ved 5 °C, deretter vann (2 x 10 ml), deretter to ganger med en blanding av mettet, vandig ammoniumklorid (15 ml) og vann (35 ml). De organiske faser tørkes på magnesiumsulfat og konsentreres til en olje. En analytisk prøve av tittelforbindelsen oppnås ved kromatografi (etylacetat/heksaner): TLC, Rf = 0,39 (etylacetat/heksaner, 25/75); HPLC rt = 8,15, 8,50 min.; NMR (CDCI3) 8,15-7,85, 7,48-7,01, 3,99, 3,92, 3,78, 3,50-3,39, 3,38, 3,32-1,21, 0,82 og 0,74-0,67 8; CMR (CDCI3), To a mixture of (3S),(7R)-4-carbomethoxy-3-(3-nitrophenyl)-7-(2-phenylethyl)-7-[(4-phenylphenoxy)methoxy]decan-5-one (XV, example 11, 9.14 g, 83.7 wt%, 11.995 mmol) in THF (20 ml) at 23 °C is added a solution of sulfuric acid in methanol (0.524 M, 20 ml, 10.48 mmol, 0.87 equiv .). The mixture is allowed to stand at 23 °C for 22 h, and then a solution of sodium bicarbonate (3.52 g, 41.90 mmol, 3.49 eq.) in water (50 mL) is added, followed by MTBE (50 mL) . The phases are separated, and the aqueous phase is washed with MTBE (30 ml). The combined organic phases are washed with aqueous sodium hydroxide (0.5 M, 2 x 50 mL) at 5 °C, then water (2 x 10 mL), then twice with a mixture of saturated aqueous ammonium chloride (15 mL) and water (35 ml). The organic phases are dried over magnesium sulfate and concentrated to an oil. An analytical sample of the title compound is obtained by chromatography (ethyl acetate/hexanes): TLC, Rf = 0.39 (ethyl acetate/hexanes, 25/75); HPLC rt = 8.15, 8.50 min.; NMR (CDCl 3 ) 8.15-7.85, 7.48-7.01, 3.99, 3.92, 3.78, 3.50-3.39, 3.38, 3.32-1, 21, 0.82 and 0.74-0.67 8; CMR (CDCI3),
205/20, 204,99, 168,00, 167,46, 148,38, 143,10, 142,04, 141,97, 135,23, 134,99, 129,47, 129,33, 128,46, 128,41, 128,28, 128,18, 125,85, 122,82, 122,58, 122,17, 73,83, 73,49, 66,63, 66,36, 52,92, 52,50, 50,79, 50,60, 46,25, 46,17, 41,57, 41,01, 40,83, 30,03, 29,60, 26,95, 17,05, 16,90, 14,55, 14,43, 11,74 og 11,47 6. 205/20, 204.99, 168.00, 167.46, 148.38, 143.10, 142.04, 141.97, 135.23, 134.99, 129.47, 129.33, 128, 46, 128.41, 128.28, 128.18, 125.85, 122.82, 122.58, 122.17, 73.83, 73.49, 66.63, 66.36, 52.92, 52.50, 50.79, 50.60, 46.25, 46.17, 41.57, 41.01, 40.83, 30.03, 29.60, 26.95, 17.05, 16, 90, 14.55, 14.43, 11.74 and 11.47 6.
Eksempel 13 Example 13
r 3a f RI, 6 i mi - 5. 6- dihvdro- 4- hvdroksv- 3- r 1- f 3- nitrof envl) - propvn- 6- r 1- f 2- fenvl) etyl1- 6- propvl- 2H- pvran- 2- on fxvil) r 3a f RI, 6 i mi - 5. 6- dihydro- 4- hvdroksv- 3- r 1- f 3- nitrof envl) - propvn- 6- r 1- f 2- phenvl) ethyl1- 6- propvl- 2H - pvran- 2- on fxvil)
En oppløsning av vandig natriumhydroksid (1 M, A solution of aqueous sodium hydroxide (1 M,
11,4 ml, 11,4 mmol, 1,89 ekv.) i metanol (35 ml) ved 4 °C tilsettes til urenset (3S),(7R)-4-karbometoksy-7-hydroksy-3-(3-nitrofenyl)-7-(2-fenyletyl)-dekan-5-on (blanding av diastereomerer ved C-4) (XVI, eksempel 12, 73,3 vekt%, 3,740 g, 6,018 mmol og skylles med metanol (45 ml) under opprettholdelse av temperaturen lavere enn 5 °C. Blandingen omrøres kraftig for a oppløse hoveddelen av den urensede olje og omrøres deretter moderat ved 0-5 °C i 67 timer. Blandingen avkjøles til -5 °C, og heksaner (90 ml) tilsettes. Fasene separeres ved < 5 °C, og den organiske fase vaskes ved < 5 °C med en blanding av metanol (50 ml) og vann (7 ml). pH i den kombinerte vandige fase justeres fra 12,55 til 6,24 ved < 5 "C med eddiksyre (1,52 g, 25,31 mmol, 4,21 ekv.). Den vandige fase konsentreres, ekstraheres med metylenklorid (2 x 40 ml), tørkes over magnesiumsulfat og konsentreres for å gi et råprodukt. Til en prøve av råproduktet (0,401 g) tilsettes eter (1,0 ml). Den resulterende oppslemming avkjøles til -30 °C, og bunnfallet oppsamles ved vakuumfiltrering, vaskes med kald eter og tørkes i en nitrogenstrøm for å gi tittelforbindelsen, TLC, Rf = 0,49 (etylacetat/heksaner, 1/1); HPLC rt = 11.4 ml, 11.4 mmol, 1.89 eq.) in methanol (35 ml) at 4 °C is added to crude (3S),(7R)-4-carbomethoxy-7-hydroxy-3-(3- nitrophenyl)-7-(2-phenylethyl)-decan-5-one (mixture of diastereomers at C-4) (XVI, Example 12, 73.3 wt%, 3.740 g, 6.018 mmol and rinsed with methanol (45 mL) while maintaining the temperature below 5 °C. The mixture is stirred vigorously to dissolve the bulk of the crude oil and then stirred moderately at 0-5 °C for 67 hours. The mixture is cooled to -5 °C and hexanes (90 mL) are added . The phases are separated at < 5 °C and the organic phase is washed at < 5 °C with a mixture of methanol (50 ml) and water (7 ml). The pH of the combined aqueous phase is adjusted from 12.55 to 6.24 at < 5 °C with acetic acid (1.52 g, 25.31 mmol, 4.21 equiv). The aqueous phase is concentrated, extracted with methylene chloride (2 x 40 mL), dried over magnesium sulfate and concentrated to give a crude product . To a sample of the crude product (0.401 g) is added ether (1.0 mL). The resulting slurry is cooled to -30 °C, and the precipitate collected by vacuum filtration, washed with cold ether and dried in a stream of nitrogen to give the title compound, TLC, Rf = 0.49 (ethyl acetate/hexanes, 1/1); HPLC rt =
6,93 min.; NMR (CDCI3/CD3OD, 1/1) 8,08, 7,80, 7,56, 7,22, 7,07-6,88, 3,98, 3,33-3,30, 2,50-2,37, 1,92-1,70, 1,58-1,50, 1,22-1,14, 0,76 og 0,72 8; CMR (CDCI3/CD3OD, 1/1) 169,05, 166,66, 148,66, 147,79, 141,99, 135,30, 129,21, 129,02, 128,70, 126,55, 123,51, 121,23, 105,13, 81,39, 42,58, 40,39, 40,09, 36,76, 30,38, 24,95, 17,44, 14,54 og 13,04 8. 6.93 min.; NMR (CDCl 3 /CD 3 OD, 1/1) 8.08, 7.80, 7.56, 7.22, 7.07-6.88, 3.98, 3.33-3.30, 2.50- 2.37, 1.92-1.70, 1.58-1.50, 1.22-1.14, 0.76 and 0.72 8; CMR (CDCI3/CD3OD, 1/1) 169.05, 166.66, 148.66, 147.79, 141.99, 135.30, 129.21, 129.02, 128.70, 126.55, 123.51, 121.23, 105.13, 81.39, 42.58, 40.39, 40.09, 36.76, 30.38, 24.95, 17.44, 14.54 and 13, 04 8.
Eksempel 14 Example 14
f 3ot( IO . 6( R)- 3 f l-( 3- aminofenvl) propvl 1 - 5, 6- dihvdro- 4- hvdroksv-6- r 1- f 2- fenvl) etyl1- 6- propvl- 2H- Pvran- 2- on t XVI11) f 3ot( IO . 6( R)- 3 f l-( 3- aminophenvl) propvl 1 - 5, 6- dihydro- 4- hvdroxv-6- r 1- f 2- phenvl) ethyl1- 6- propvl- 2H- Pvran- 2- on t XVI11)
Til en oppløsning av [3a{R),6(R)]-5,e-dihydro^-hydroksy-S-t l-(3-nitrofenyl)propyl]-6-[l-(2-fenyl)etyl]-6-propyl-2H-pyran-2-on (XVII, eksempel 13, 0,6993 g, 1,651 mmol) i THF (50 ml) tilsettes palladium-på-karbon (5 %, 50 % vann, 0,2574 g, 0,06048 mmol, 0,0366 ekv.)» og blandingen hydrogeneres ved 3,5 kg/cm<2> på et Parr-risteapparat i 21 timer. Celitt (2,07 g) tilsettes, og katalysatoren fjernes ved vakuumfiltrering og skylles med THF. Filtratet konsentreres for å gi tittelforbindelsen, TLC, Rf = 0,45 (etylacetat/heksaner, 1/1); HPLC rt = 5,18 min. To a solution of [3a{R),6(R)]-5,e-dihydro^-hydroxy-S-t 1-(3-nitrophenyl)propyl]-6-[1-(2-phenyl)ethyl]-6 -propyl-2H-pyran-2-one (XVII, Example 13, 0.6993 g, 1.651 mmol) in THF (50 mL) is added palladium-on-carbon (5%, 50% water, 0.2574 g, 0 .06048 mmol, 0.0366 eq.)" and the mixture is hydrogenated at 3.5 kg/cm<2> on a Parr shaker for 21 hours. Celite (2.07 g) is added and the catalyst is removed by vacuum filtration and rinsed with THF. The filtrate is concentrated to give the title compound, TLC, Rf = 0.45 (ethyl acetate/hexanes, 1/1); HPLC rt = 5.18 min.
Eksempel 15 Example 15
f R-( R*. R* ) 1- N- f 3- r 1- r 5. 6- dihvdro- 4- hvdroksv- 2- okso- 6-(2-fenvletyl)- 6- propvl- 2H- pvran- 3- vlIpropyl1fenyl1- 5-( trifluor-metyl) - 2- pyridinsulfonamid fXIX) f R-( R*. R* ) 1- N- f 3- r 1- r 5. 6- dihydro- 4- hydroxy- 2- oxo- 6-(2-phenvletyl)- 6- propvl- 2H- pvran - 3- vlIpropyl1phenyl1- 5-( trifluoro-methyl) - 2- pyridinesulfonamide fXIX)
Til en blanding av [3a(R),6R]-3-[l-(3-aminofenyl)-propyl]-5,6-dihydro-4-hydroksy-6-[l-(2-fenyl)etyl]-6-propyl-2H-pyran-2-on (XVIII, eksempel 14, urenset 0,555 g, To a mixture of [3a(R),6R]-3-[1-(3-aminophenyl)-propyl]-5,6-dihydro-4-hydroxy-6-[1-(2-phenyl)ethyl]- 6-propyl-2H-pyran-2-one (XVIII, Example 14, crude 0.555 g,
1,378 mmol, basert på tittelforbindelsen XIX) i metylenklorid (3,10 ml), DMSO (0,100 ml, 1,409 mmol, 1,02 ekv.) og pyridin (0,56 ml, 6,92 mmol, 5,02 ekv.) tilsettes råblandingen av 5-trifluormetyl)-2-pyridinsulfonylklorid i metylenklorid, fremstilt ovenfor (5,23 ml, ca. 2,3 mmol, basert på tiol, ca. 1.378 mmol, based on the title compound XIX) in methylene chloride (3.10 mL), DMSO (0.100 mL, 1.409 mmol, 1.02 equiv) and pyridine (0.56 mL, 6.92 mmol, 5.02 equiv) is added to the crude mixture of 5-trifluoromethyl)-2-pyridinesulfonyl chloride in methylene chloride, prepared above (5.23 ml, approx. 2.3 mmol, based on thiol, approx.
1,7 ekv.) ved -25 til -30 °C i løpet av 2 timer, etterfulgt av titrering med 5-(trifluormetyl)-2-pyridinsulfonylkloridbland-ingen til et HPLC-endepunkt på 1,4 arealprosent resterende [3a(R),6R]-3-[1-(3-aminofenyl)propyl]-5,6-dihydro-4-hydroksy-6-[l-(2-fenyl)etyl]-6-propyl-2H-pyran-2-on (XVIII, eksempel 14). Vandig saltsyre (1 M, 6,2 ml, 6,2 mmol, 4,50 ekv.) og etylacetat (5,2 ml) tilsettes, og fasene separeres. Den vandige fase vaskes med metylenklorid (10 ml), og de kombinerte organiske faser tørkes på magnesiumsulfat og konsentreres. Konsentratet appliseres på en kiselgelkolonne (9,76 g kiselgel) pakket med etylacetat/heksaner (10/90), og produktet elueres med de følgende blandinger av etylacetat i heksaner (50 ml 10 %, 100 ml 20 %, 100 ml 30 % og 50 ml 40 %). 1.7 eq.) at -25 to -30 °C over 2 h, followed by titration with the 5-(trifluoromethyl)-2-pyridinesulfonyl chloride mixture to an HPLC endpoint of 1.4 area percent remaining [3a(R ),6R]-3-[1-(3-aminophenyl)propyl]-5,6-dihydro-4-hydroxy-6-[1-(2-phenyl)ethyl]-6-propyl-2H-pyran-2 -on (XVIII, example 14). Aqueous hydrochloric acid (1 M, 6.2 mL, 6.2 mmol, 4.50 equiv) and ethyl acetate (5.2 mL) are added and the phases are separated. The aqueous phase is washed with methylene chloride (10 mL), and the combined organic phases are dried over magnesium sulfate and concentrated. The concentrate is applied to a silica gel column (9.76 g silica gel) packed with ethyl acetate/hexanes (10/90), and the product is eluted with the following mixtures of ethyl acetate in hexanes (50 ml 10%, 100 ml 20%, 100 ml 30% and 50 ml 40%).
Elueringsmidlet kombineres og konsentreres til en olje ved hjelp av etylacetat. Etylacetat tilsettes (5,2 ml), og produktet utfelles ved langsom tilsetning av heptan (15 ml). Den resulterende oppslemming avkjøles til -30 °C, og bunnfallet oppsamles ved vakuumfiltrering, vaskes ved -30 °C med en blanding av etylacetat (1 ml) og heptan (4 ml) og tørkes i en nitrogenstrøm for å gi tittelforbindelsen, smp. = 86-89 °C; TLC, Rf = 0,66 (etylacetat/heksan, 50/50); NMR (CD3OD) 8,94, 8,19, 8,02, 7,25-6,97, 3,93, 2,68-2,52, 2,15-2,09, 1,96-1,64, 1,33, 0,88 og 0,83 8; CMR (CD30D) 169,9, 167,0, 161,6, 148,1, 147,6, 142,8, 137,7, 137,0, 130,1, 129,5, 129,3, 127,0, 126,1, 124,2, 122,6, 120,3, 106,2, 81,9, 43,6, 40,5, 40,5, 37,4, 30,9, 25,8, 17,9, 14,7 og 13,3 8; MS (CI, ammoniakk) m/z (relativ intensitet) 621 (1,7), 620 (5,4), 604 (1,1), 603 (3,4), 411 (12), 394 (12), 148 (100); IR (mull) 1596, 1413 1359, 1326, 1177, 1149, 1074 og 720 cm"<1> (samme faste til-stands f orm som referansen). The eluent is combined and concentrated to an oil using ethyl acetate. Ethyl acetate (5.2 ml) is added, and the product is precipitated by slow addition of heptane (15 ml). The resulting slurry is cooled to -30 °C and the precipitate collected by vacuum filtration, washed at -30 °C with a mixture of ethyl acetate (1 ml) and heptane (4 ml) and dried in a stream of nitrogen to give the title compound, m.p. = 86-89 °C; TLC, Rf = 0.66 (ethyl acetate/hexane, 50/50); NMR (CD 3 OD) 8.94, 8.19, 8.02, 7.25-6.97, 3.93, 2.68-2.52, 2.15-2.09, 1.96-1, 64, 1.33, 0.88 and 0.83 8; CMR (CD30D) 169.9, 167.0, 161.6, 148.1, 147.6, 142.8, 137.7, 137.0, 130.1, 129.5, 129.3, 127, 0, 126.1, 124.2, 122.6, 120.3, 106.2, 81.9, 43.6, 40.5, 40.5, 37.4, 30.9, 25.8, 17.9, 14.7 and 13.3 8; MS (Cl, ammonia) m/z (relative intensity) 621 (1.7), 620 (5.4), 604 (1.1), 603 (3.4), 411 (12), 394 (12) , 148 (100); IR (mull) 1596, 1413 1359, 1326, 1177, 1149, 1074 and 720 cm"<1> (same solid state form as the reference).
Eksempel 16 Example 16
r 3a( R), 6( R) 1- 5, 6- dihvdro- 4- hvdroksv- 3- r l3 - nitrofenvl)-propenyl1- 6- fl-( 2- fenyl) etyl1- 6- propvl- 2H- pvran- 2- on fXXV, hovedkomponent) oa r 3a( R\. 6R1 - 5. 6- dihydro- 4- hydroksv- 3- r f E)-1-( 3- nitrofenylipropenyl1- 6- rl-( 2- fenylletvl1- 6- propvl- 2H- pyran-2- on fXXV, bikomponent) r 3a( R), 6( R) 1- 5, 6- dihydro- 4- hydroxy- 3- r 13 - nitrophenyl)-propenyl1- 6- fl-(2- phenyl) ethyl1- 6- propvl- 2H- pvran - 2- on fXXV, main component) oa r 3a( R\. 6R1 - 5. 6- dihydro- 4- hydroxyv- 3- r f E)-1-( 3- nitrophenylipropenyl1- 6- rl-( 2- phenylletvl1- 6 - propvl- 2H- pyran-2- one fXXV, bicomponent)
(6R)-5,6-dihydro-4-hydroksy-6-[l-(2-fenyl)etyl]-6-propyl-2H-pyran-2-on (VI, eksempel 4, 50,0 g, 187 mmol) kombineres med m-nitropropiofenon (33,5 g, 187,2 mmol) og 375 ml THF. Pyridin tilsettes (31,0 ml, 374 mmol), og den resulterende blanding omrøres og avkjøles til lavere enn -5 °C. En løsning prepareres ved tilsetning av titantetraklorid (31 ml, 280 mmol) til 80 ml toluen, og denne løsningen tilsettes til blandingen på en kontrollert måte for å opprettholde reaksjonstemperaturen lavere enn 10 °C. Toluen (15 ml) anvendes som skyllemiddel i titantetrakloridløsningen, og ved slutten av denne tilsetning oppvarmes reaksjonsblandingen til mellom 35 og 45 °C og opprettholdes i dette området i ca. 16 timer. Reaksjonsblandingen avkjøles til 0 °C, og vann (200 ml) tilsettes i en enkelt porsjon. Denne blandingen omrøres inntil alt fast materiale er oppløst. Blandingen oppvarmes til minst 15 °C og overføres deretter til en skilletrakt ved' anvendelse av vann (250 ml) og etylacetat (500 ml) for å fortynne blandingen. Det vandige lag separeres, fjernes, ekstraheres med etylacetat (150 ml) og kastes. Det primære organiske lag vaskes sekvensielt med saltsyre (IN, 2 x 150 ml), vann (150 ml) og mettet natriumbikarbonat (150 ml). Hver vaske-løsning ekstraheres med etylacetatekstrakten (150 ml) før den kastes. Ved dette punkt kombineres det primære organiske lag og ekstrakten og konsentreres under redusert trykk for å gi et konsentrat. Konsentratet oppløses deretter i metylenklorid (350 ml). Denne løsningen ekstraheres med totalt 500 ml 1 N natriumhydroksid (4 x 50 ml, deretter 3 x 100 ml). De kombinerte vandige ekstrakter vaskes med totalt 500 ml metylenklorid (4 x 50 ml, deretter 3 x 100 ml) og behandles deretter med saltsyre (3 N, 150 ml). Den surgjorte blanding ekstraheres med metylenklorid (400 ml, deretter 6 x 100 ml), og de kombinerte organiske ekstrakter vaskes med vann (200 ml) og deretter saltvann (200 ml). Etter etterfølgende tørking med vannfritt natriumsulfat filtreres blandingen gjennom et lag av magnesol og konsentreres deretter under redusert trykk for å gi blandingen av tittelforbindelsene, TLC, Rf - 0,18 for (Z)-isomer, 0,28 for (E)-isomer (etylacetat/heksan, 1/1); CMR (CDC13) 166,93, 166,53, 148,27, 142,53, 142,39, 140,96, 132,23, 132,12, 131,82, 131,74, 129,87, 129,12, 128,55, 128,14, 126,16, 121,67, 120,56, 101,09, 81,77, 39,78, 35,23, 29,73, 16,91, 15,75, 15,69 og 14,23 8; MS (CI + NH3) m/z (relativ intensitet) 439 (100), 422 (18), 409 (9), 392 (9), 278 (9), 194 (10), 136 (9). (6R)-5,6-dihydro-4-hydroxy-6-[1-(2-phenyl)ethyl]-6-propyl-2H-pyran-2-one (VI, Example 4, 50.0 g, 187 mmol) is combined with m-nitropropiophenone (33.5 g, 187.2 mmol) and 375 mL of THF. Add pyridine (31.0 mL, 374 mmol), and the resulting mixture is stirred and cooled to less than -5 °C. A solution is prepared by adding titanium tetrachloride (31 mL, 280 mmol) to 80 mL of toluene, and this solution is added to the mixture in a controlled manner to maintain the reaction temperature below 10 °C. Toluene (15 ml) is used as a rinse agent in the titanium tetrachloride solution, and at the end of this addition, the reaction mixture is heated to between 35 and 45 °C and maintained in this range for approx. 16 hours. The reaction mixture is cooled to 0 °C and water (200 mL) is added in a single portion. This mixture is stirred until all solid material is dissolved. The mixture is heated to at least 15°C and then transferred to a separatory funnel using water (250 mL) and ethyl acetate (500 mL) to dilute the mixture. The aqueous layer is separated, removed, extracted with ethyl acetate (150 mL) and discarded. The primary organic layer is washed sequentially with hydrochloric acid (IN, 2 x 150 mL), water (150 mL), and saturated sodium bicarbonate (150 mL). Each wash solution is extracted with the ethyl acetate extract (150 ml) before being discarded. At this point the primary organic layer and extract are combined and concentrated under reduced pressure to give a concentrate. The concentrate is then dissolved in methylene chloride (350 ml). This solution is extracted with a total of 500 ml of 1 N sodium hydroxide (4 x 50 ml, then 3 x 100 ml). The combined aqueous extracts are washed with a total of 500 ml of methylene chloride (4 x 50 ml, then 3 x 100 ml) and then treated with hydrochloric acid (3 N, 150 ml). The acidified mixture is extracted with methylene chloride (400 mL, then 6 x 100 mL), and the combined organic extracts are washed with water (200 mL) and then brine (200 mL). After subsequent drying with anhydrous sodium sulfate, the mixture is filtered through a pad of magnesol and then concentrated under reduced pressure to give the mixture of the title compounds, TLC, Rf - 0.18 for (Z) isomer, 0.28 for (E) isomer ( ethyl acetate/hexane, 1/1); CMR (CDC13) 166.93, 166.53, 148.27, 142.53, 142.39, 140.96, 132.23, 132.12, 131.82, 131.74, 129.87, 129, 12, 128.55, 128.14, 126.16, 121.67, 120.56, 101.09, 81.77, 39.78, 35.23, 29.73, 16.91, 15.75, 15.69 and 14.23 8; MS (Cl + NH 3 ) m/z (relative intensity) 439 (100), 422 (18), 409 (9), 392 (9), 278 (9), 194 (10), 136 (9).
Eksempel 17 Example 17
f 3af R). 6( Rn- 5. 6- dihvdro- 4- hvdroksv- 3- f1-( 3- nitrofenvl\-propvl1- 6Tr l - t 2- fenvl) etvn- 6- propvl- 2H- pvran- 2- on f XVII \ f 3of R). 6( Rn- 5. 6- dihydro- 4- hvdroxv- 3- f1-( 3- nitrophenvl\-propvl1- 6Tr l - t 2- phenvl) etvn- 6- propvl- 2H- pvran- 2- one f XVII \
[ 3a (R),6{R)-5,6-dihydro-4-hydroksy-3-[(Z)-1-(3-nitrofenyl)propenyl]-6-[l-(2- fenyl)etyl]-6-propyl-2H-pyran-2-on (XXV, eksempel 16, 4,24 g, 10 mmol) og [{1,5-syklooktadien)-rhodium(I)-1,2-bis-{2R,5R)-dimetylfosfolano)benzen]tetrafluor-borat (6,0 mg, 0,01 mmol) kombineres i en inert atmosfære og oppløses i 20 ml deoksygenert metanol. Atmosfæren erstattes med hydrogen ved et trykk på 5,6 kg/cm<2> eller høyere, og [ 3a (R),6{R)-5,6-dihydro-4-hydroxy-3-[(Z)-1-(3-nitrophenyl)propenyl]-6-[1-(2-phenyl)ethyl] -6-propyl-2H-pyran-2-one (XXV, Example 16, 4.24 g, 10 mmol) and [{1,5-cyclooctadiene)-rhodium(I)-1,2-bis-{2R, 5R)-Dimethylphospholano)benzene]tetrafluoroborate (6.0 mg, 0.01 mmol) is combined under an inert atmosphere and dissolved in 20 mL of deoxygenated methanol. The atmosphere is replaced with hydrogen at a pressure of 5.6 kg/cm<2> or higher, and
reaksjonsblandingen oppvarmes til 55 °C og omrøres i 24 timer. Ved slutten av denne perioden avkjøles reaksjonsblandingen til 20-25 °C, og hydrogen erstattes med en inert atmosfære. Reaksjonsblandingen konsentreres under redusert trykk, og resten krystalliseres fra en metanol-/vannblanding (3/1) for å gi tittelforbindelsen, TLC, Rf = 0,49 (etylacetat/heksaner, 1/1); HPLC rt = 6,93 min.; NMR (CDCI3/CD3OD, 1/1) 8,08, 7,80, 7,56, 7,22, 7,07-6,88, 3,98, 3,33-3,30, 2,50-2,37, 1,92-1,70, 1,58-1,50, 1,22-1,14, 0,76 og 0,72 6; CMR (CDCL13/CD30D, 1/1) 169,05, 166,66, 148,66, 147,79, 141,99, 135,30, 129,21, 129,02, 128,70, 126,55, 123,51, 121,23, 105,13, 81,39, 42,58, 40,39, 40,09, 36,76, 30,38, 24,95, 17,44, 14,54 og 13,04 5. the reaction mixture is heated to 55 °C and stirred for 24 hours. At the end of this period, the reaction mixture is cooled to 20-25 °C, and hydrogen is replaced with an inert atmosphere. The reaction mixture is concentrated under reduced pressure and the residue crystallized from a methanol/water mixture (3/1) to give the title compound, TLC, Rf = 0.49 (ethyl acetate/hexanes, 1/1); HPLC rt = 6.93 min.; NMR (CDCl 3 /CD 3 OD, 1/1) 8.08, 7.80, 7.56, 7.22, 7.07-6.88, 3.98, 3.33-3.30, 2.50- 2.37, 1.92-1.70, 1.58-1.50, 1.22-1.14, 0.76 and 0.72 6; CMR (CDCL13/CD30D, 1/1) 169.05, 166.66, 148.66, 147.79, 141.99, 135.30, 129.21, 129.02, 128.70, 126.55, 123.51, 121.23, 105.13, 81.39, 42.58, 40.39, 40.09, 36.76, 30.38, 24.95, 17.44, 14.54 and 13, 04 5.
Eksempel 18 Example 18
( 6R) - 5, 6- dihvdro- 4- hydroksv- 6- r l-( 2- f envl) etvn- 6- propvl- 2H-p yran- 2- on fCVI) ( 6R) - 5, 6- dihydro- 4- hydroxysv- 6- r 1-( 2- f envl) etvn- 6- propvl- 2H-pyran- 2- one fCVI)
(R)-3-hydroksy-3-(2-fenyletyl)heksansyre, (IR,2S)-norefedrinsalt (CIV, 180 g; 486 mmol) omdannes til (R)-3-hydroksy-3-(2-fenyletyl)heksansyre ved oppslemming av saltet i metylenklorid (1100 ml) og tilsetning av saltsyre (2 M, (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid, (IR,2S)-norephedrine salt (CIV, 180 g; 486 mmol) is converted to (R)-3-hydroxy-3-(2-phenylethyl) hexanoic acid by suspending the salt in methylene chloride (1100 ml) and adding hydrochloric acid (2 M,
720 ml), den frie syre ekstraheres med metylenklorid, og blandingen tørkes azeotropt ved atmosfærisk destillasjon med trinnvis tilsetning av metylenklorid (700 ml totalt). Den frie syreblanding (350 ml) tilsettes til en oppslemming av karbonyldiimidazol (90,5 g, 558 mmol) i metylenklorid (80 ml) og pyridin (210 ml) ved -10 til 0 °C. Blandingen oppvarmes til 720 ml), the free acid is extracted with methylene chloride, and the mixture is dried azeotropically by atmospheric distillation with stepwise addition of methylene chloride (700 ml in total). The free acid mixture (350 mL) is added to a slurry of carbonyldiimidazole (90.5 g, 558 mmol) in methylene chloride (80 mL) and pyridine (210 mL) at -10 to 0 °C. The mixture is heated to
0 °C og omrøres i 1 time. 0 °C and stirred for 1 hour.
En oppslemming av malonatmonoetylestermagnesiumsalt prepareres ved tilsetning av en acetonoppslemming av kalium-malonatmonoetylester (144 g, 846 mmol i 350 ml aceton) til en oppslemming av magnesiumklorid (72 g, 756 mmol) som er blitt preparert ved langsom tilsetning av aceton (250 ml) til en oppslemming av magnesiumklorid i metylenklorid (100 ml). Prepareringen av malonatsaltet fullføres ved atmosfærisk destillasjon til et volum på 350 ml. A slurry of malonate monoethyl ester magnesium salt is prepared by adding an acetone slurry of potassium malonate monoethyl ester (144 g, 846 mmol in 350 mL acetone) to a slurry of magnesium chloride (72 g, 756 mmol) which has been prepared by slowly adding acetone (250 mL) to a slurry of magnesium chloride in methylene chloride (100 ml). The preparation of the malonate salt is completed by atmospheric distillation to a volume of 350 ml.
(R)-3-hydroksy-3-(2-fenylety1)heksanoy1imidazo1-blandingen fra karbonyldiimidazolaktiveringen tilsettes til magnesiumetyImalonatoppslemmingen ved 10-20 °C. Blandingen oppvarmes til 20-25 °C og omrøres i ca. 16 timer. Reaksjonen The (R)-3-hydroxy-3-(2-phenylethyl)hexanoyl imidazo mixture from the carbonyldiimidazole activation is added to the magnesium ethyl malonate slurry at 10-20 °C. The mixture is heated to 20-25 °C and stirred for approx. 16 hours. The reaction
stanses ved tilsetning av saltsyre (5 N, 850 ml). Metylenklorid (125 ml) tilsettes, og fasene separeres. Det produktinneholdende organiske lag vaskes med saltsyre (1 N, 400 ml) og deretter med mettet natriumbikarbonatløsning (500 ml). De organiske faser konsentreres under vakuum til ca. 200 ml, metanol (700 ml) tilsettes, og vakuumkonsentrasjonen fort-settes til et sluttvolum på 150 ml. Til den metanoliske opp-løsning av (R)-etyl-5-hydroksy-3-okso-5-(2-fenyletyl)oktanoat tilsettes en metanolisk oppløsning av kaliumhydroksid (59,5 g, 85 %; 902 mmol oppløst i 200 ml metanol) ved 15-20 °C. Blandingen omrøres i 16 timer ved 20 °C. Vann (350 ml) tilsettes, og det produktinneholdende vandige lag vaskes to ganger med metyl-t-butyleter (350 ml for hver vask). Den vandige fase surgjøres med saltsyre (6 M, 220 ml), og produktet ekstraheres med toluen (550 ml). Toluenblandingen vaskes med vann (150 ml) og konsentreres under redusert trykk til 200 ml. Produktet krystalliseres ved tilsetning av forgrenet oktan (ca. 400 ml i to porsjoner som tillater krystallisering mellom tilsetningene). Ved avkjøling isoleres produktet ved vakuumfiltrering, vaskes med forgrenet oktan og tørkes ved 20-25 °C for å gi tittelforbindelsen. quenched by the addition of hydrochloric acid (5 N, 850 ml). Methylene chloride (125 ml) is added and the phases are separated. The product-containing organic layer is washed with hydrochloric acid (1 N, 400 ml) and then with saturated sodium bicarbonate solution (500 ml). The organic phases are concentrated under vacuum to approx. 200 ml, methanol (700 ml) is added and the vacuum concentration is continued to a final volume of 150 ml. To the methanolic solution of (R)-ethyl-5-hydroxy-3-oxo-5-(2-phenylethyl)octanoate is added a methanolic solution of potassium hydroxide (59.5 g, 85%; 902 mmol dissolved in 200 ml methanol) at 15-20 °C. The mixture is stirred for 16 hours at 20 °C. Water (350 ml) is added and the product-containing aqueous layer is washed twice with methyl t-butyl ether (350 ml for each wash). The aqueous phase is acidified with hydrochloric acid (6 M, 220 ml), and the product is extracted with toluene (550 ml). The toluene mixture is washed with water (150 ml) and concentrated under reduced pressure to 200 ml. The product is crystallized by adding branched octane (approx. 400 ml in two portions that allow crystallization between the additions). On cooling, the product is isolated by vacuum filtration, washed with branched octane and dried at 20-25 °C to give the title compound.
Eksempel 19 Example 19
5. 6- dihvdro- 4- hvdroksv- 6- r1-( 2- f 4- substituert) fenyl) etvl1- 6-isopropyl- 2H- pyran- 2- oner ( CVI) 5. 6- dihydro- 4- hydroxy- 6- r1-(2- f 4- substituted) phenyl) etvl1- 6- isopropyl- 2H- pyran- 2-one (CVI)
Ved å følge de generelle prosedyrer ifølge eksempler 1-4 og utføre ikke-kritiske variasjoner, men med start med 4-hydroksy-, 4-amino-, 4-monoalkylamino- eller 4-dialkylamino-fenyl-2-metyl-3-pentanon (CI), oppnås tittelforbindelsen. By following the general procedures of Examples 1-4 and performing non-critical variations, but starting with 4-hydroxy-, 4-amino-, 4-monoalkylamino- or 4-dialkylamino-phenyl-2-methyl-3-pentanone (CI), the title compound is obtained.
Eksempel 20 Example 20
1 6S)- 5. 6- dihvdro- 4- hvdroksv- 6- r W 2- fenyl) etvl1- 6- fenvl- 2H-pyran- 2- oner fCVI) 1 6S)- 5. 6- dihydro- 4- hydroxy- 6- r W 2- phenyl) etvl1- 6- phenvl- 2H-pyran- 2-one fCVI)
Ved å følge den generelle prosedyre ifølge eksempler 1-4 og utføre ikke-kritiske variasjoner, men med start med 1,3-difenyl-l-propanon (CI), oppnås tittelforbindelsen. By following the general procedure of Examples 1-4 and performing non-critical variations, but starting with 1,3-diphenyl-1-propanone (CI), the title compound is obtained.
Eksempel 21 Example 21
t- butvl- 3- hvdroksy- 3-( 2- fenyletylIheksanoate ( II) t-butyl-3-hydroxy-3-(2-phenylethylhexanoate (II)
Ved å følge den generelle prosedyre ifølge eksempel 1 og utføre ikke-kritiske variasjoner, men ved anvendelse av t-butylacetat istedenfor etylacetat, oppnås tittelforbindelsen. Det er foretrukket at t-butylacetat anvendes. By following the general procedure of Example 1 and making non-critical variations, but using t-butyl acetate instead of ethyl acetate, the title compound is obtained. It is preferred that t-butyl acetate is used.
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